HIV protease inhibitors

ABSTRACT

The present invention relates to novel dihydropyrones with tethered heterocycles having improved pharmacologic properties which potently inhibit the HIV aspartyl protease blocking HIV infectivity. The dihydropyrones are useful in the development of therapies for the treatment of viral infections and diseases, including AIDS. The present invention is also directed to methods of synthesis of the dihydropyrones and intermediates useful in the preparation of the final compounds.

This application is a division of the U.S. application Ser. No.09/674,652 filed Nov. 2, 2000 now U.S. Pat. No. 6,528,510, which is a371 of PCT/US99/18986 filed Aug. 18, 1999 which claims benefit of U.S.Application Ser. No. 60/099946 filed Sep. 11, 1998.

BACKGROUND OF THE INVENTION

The HIV-protease enzyme is absolutely essential for the replication anddissemination of HIV throughout the body (Navia M. A. and McKeever B.M., Ann. New York Acad. Sci., 1990;616:73-85) and has become anextremely important target for the design and development of anti-HIVtherapeutic agents (von der Helm K., Biol. Chem. 1996;377:756-774).Several peptidomimetic HIV protease inhibitors have been successfullydeveloped (such as indinavir, saquinavir, ritonavir, and nelfinavir),which demonstrate significant clinical success in lowering plasma viralload, reducing the onset to AIDS, and decreasing the frequency ofopportunistic infections (Deeks S. G., Smith M., Holodniy M., and KahnJ. O., JAMA., 1997;277:145-153).

Yet the current HIV protease inhibitors by their peptidomimetic naturehave relatively poor solubility, high biliary excretion, limitedbioavailabilities and significant liver metabolism. These drawbacks inturn increase the need for high doses of drug which increases thefrequency of various side effects and multiple drug interactions (BarryM., Gibbons S., Back D., and Mulcahy F., Clin. Pharmacokinet.,1997;32:194-209). More importantly, resistance to the current HIVprotease inhibitors has emerged (Shock H. B., Garsky V. M., and Kuo L.,J. Biol. Chem., 1996;271:3 1957-31963) resulting in treatment failures(Fatkenheuer G., Theisen A., Rockstroh J., Grabow T., et al., AIDS,1997;11:F113-F116). From this discussion, it is apparent that while HIVprotease is an excellent antiviral target for the treatment of HIVinfection and AIDS, there is a critical need to identify non-peptideinhibitors with improved pharmacological properties and which are notcross resistant with the current drugs (Wallace R. W., DDT,1997;2:83-84).

U.S. Pat. No. 5,789,440 recites non-peptidic HIV protease inhibitors offormula A

The patent application is hereby incorporated by reference. ExcellentHIV protease inhibition was achieved, but the antiviral activity at thecellular level was in some cases less than desired for an idealtherapeutic agent due to poor overall pharmacological properties(Tummino P. J., Vara Prasad J. V. N., Ferguson D., Nauhan C., et al.,BioOrganic and Med. Chem., 1996;4:1401-1410). These efforts however ledto a core structure B where R₁ and R₂ were alkyl groups filling the

S₁′ and S₂′ pockets, respectively, and the phenyl of the phenethyl groupat C₆ filled the S₂ pocket very efficiently. This core structure wasrecognized as a valuable platform for additional study (Tait B. D.,Hagen S., Domagala J. M., Ellsworth E. L., et al., J. Med. Chem.,1997;40:3781-3792).

Additional dihydropyrones C were reported when it was unexpectedlydiscovered that certain polar groups judiciously placed at R₁-R₅ led togreatly

improved antiviral cellular activity. See U.S. patent application Ser.No. 08/883,743. The patent application is hereby incorporated byreference. Among the preferred compounds were those where R₁ and R₅ wereOH, NH₂, or CH₂OH. In such cases, the preferred R₄ included a smallalkyl chain or ring and R₆ was methyl. In addition to improved cellularantiviral activity, the compounds also showed good pharmacokinetics inanimals relative to the non-polar substituted compounds. These compoundswere also not cross resistant with current HIV Protease inhibitors(Hagen S. E., Vara Prasad J. V. N., Boyer F. E., Domagala J. M., et al.,J. Med., 1997;40:3707-3711; Vander Roest S., Wold S., and Saunders J.,37th Interscience Conference on Antimicrobial Agents and Chemotherapy,Sep. 28-Oct. 1, 1997, Toronto, Canada. Abstract I-84; Domagala J. M.,Boyer F., Ellsworth E., Gajda C., et al., 5^(th) Conference onRetroviruses and Opportunistic Infections, Feb. 1-5, 1998, Chicago, Ill.Abstract 638).

While the compounds C were notable for their improved pharmacologicalproperties relative to the non-polar substituted core molecules B, thesehighly favorable properties were conferred directly by the use of OH,NH₂ and NR₂ groups placed on the lipophilic rings. The rings themselveswere important for binding to the enzyme “pockets” and for holding thet-butyl group and the groups R₁-R₃ and R₅ in their proper places withinthe enzyme's active site.

It is well-known in the pharmacological sciences that OH and NH₂ groups,especially phenols and anilines, offer distinct metabolic sitesresulting in deactivation of the drug and more rapid clearance. Inparticular, phenols may be glucuronidated and amines and anilines aresubstrates for rapid acetylation (Goodman L. S. and Gilman A., ThePharmacological Basis of Therapeutics, Permagon Press, New York, N.Y.1985: 13-16). Such modifications generally inactivate the drug bypreventing its binding to the structurally stringent active site of theenzyme. The modifications also reduce the plasma level of the activeagent (Caldwell J., in Concepts in Drug Metabolism, edited by Jenner P.and Testa B., Marcel Dekker, New York, N.Y., Part A, 1980:235-238).Another suggested problem with amines and anilines is their possibleoxidation to electropositive nitrogen species which have mutagenicpotential (Sobels F. H. Mut. Res., 1985;157:107-110; Bus J. S. and PoppJ. A., Fd Chem. Toxic. 1987;25:619-626; Rodrigues-Arnaiz R. and ArandaJ. H., Env. Mol. Mutagenesis, 1994;24:75-79). Thus, while the polargroups are vital for good antiviral efficacy, solubility, and oralabsorption, they also present sites for metabolism and possiblemutagenesis.

This hereby incorporates by reference 5888L1-01-TMC filed on even dateherewith now U.S. Patent Application Ser. No. 60/099,944 filed Sep. 11,1998, entitled “A Method of Making Dihydropyrone HIV ProteaseInhibitors” by Victor Fedij, et al.

SUMMARY OF THE INVENTION

The present invention relates to the extraordinary discovery that thephenyl groups bearing the important polar groups (especially the OH andNH₂ groups) in formula C above, the very polar groups that improvedcellular antiviral activity and improved pharmacokinetics in animalsrelative to compounds of formula B, can themselves be replaced bycertain selected heterocycles. These heterocycles bind to the enzyme inthe manner of the phenyls to preserve essential enzymatic activity, butadditionally present the polar atoms of the heterocycle in such a way asto maintain cellular antiviral activity without requiring peripheral OHand NH₂ groups. Since these compounds have fewer peripheral OH and NH₂groups, they have even greater pharmacokinetic improvements and lesspotential for amine based toxicity.

The dihydropyrones with selected heterocycles replacing the phenylsbearing polar substituents are useful in the development of treatmentsfor infections caused by viruses, especially by retroviruses that relyon aspartyl protease activities for replication and infectivity. Onesuch virus is HIV. These dihydropyrones provide higher plasma levels inanimals and man due to reduced metabolism and/or clearance, and theyprovide less toxicity risk due to the removal of certain reactiveanilino functionalities. For these reasons, the compounds of thisinvention are very useful for lowering viral load in individualsinfected with HIV. Furthermore, the compounds reduce diseases andsyndromes associated with viral pathogenesis. One such syndrome is AIDS.

The compounds of the instant invention will be useful according to:Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adultsand Adolescents, supplement to the J. of the International Associationof Physicians in AIDS Care, Supp. No. 1, Vol. 5, pp 4-26 and David A.Katzenstein, Antiretroviral Therapy for HIV: What to do in 1999. TheJournal of Critical Illness, April 1999;14(4):196.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds or pharmaceuticallyacceptable salts thereof, of Formula I

-   -   R₁ is H, a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R₂ is H, a straight or branched alkyl of 1-5 carbons;    -   R₃ is H, (CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, (CR′₂)_(n)NR′COR,        (CR′₂)_(n)CO₂R, (CR′₂)_(n)OCOR, (CR′₂)_(n)CON(R)₂,        (CR′₂)_(n)OCON(R)₂, (CR′₂)_(n)R, (CR′₂)_(n)NR′CON(R)₂,        (CR′₂)_(n)NR′CO₂R, (CR′₂)_(n)OSO₂N(R)₂, (CR′₂)_(n)NR′SO₂OR,        (CR′₂)_(n)NR′SO₂N(R)₂, (CR′₂)_(n)OSO₂R, (CR′₂)_(n)NR′SO₂R,        (CR′₂)_(n)SO_(p)R, (CR′₂)_(n)NR′CSN(R)₂,        (CR′₂)_(n)NR′C(NR′)N(R)₂, (CR′₂)_(n)SO₂N(R)₂,        (CR′₂)_(n)C(NR′)N(R)₂, (CR′₂)_(n)COR, O(CR′₂)_(m)OR,        NR(CR′₂)_(m)OR, F, Cl, Br, CF₃, CN, or ═O;    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CR′₂)_(n)OR,        (CR′₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,        (CR′₂)_(p)SO_(p)R, (CR′₂)_(p)R, (CR′₂)_(p)OCOR, O(CR′₂)_(m)OR,        NR(CR′₂)_(m)OR, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,        (CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R,        (CR′₂)_(p)CON(R)₂, (CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂,        (CR′₂)_(p)NR′SO₂OR, (CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)NR′SO₂N(R)₂,        (CR′₂)_(p)C(NR′)N(R)₂, (CR′₂)_(p)NR′C(NR′)N(R)₂, (CR′₂)_(p)Het;    -   any two of R₁-R₃ or R₄-R₆ may together form a ring of 5-6 total        atoms which may contain 0-3 heteroatoms;    -   n is an integer of from 0 to 3;    -   m is an integer of from 2 to 4;    -   p is an integer from 0 to 2;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R is independently H, a straight or branched alkyl of 1-4        carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms        containing 1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may        form a heterocycle containing the nitrogen, all optionally        substituted by F, Cl, Br, OR′, CN, CO₂R′, N(R′)₂, NR′COR′, CF₃,        or ═O;    -   R′ is independently H, a straight or branched alkyl of 1-4        carbons, or phenyl;    -   R″ is independently H, a straight or branched alkyl of 1-4        carbons, F, Cl, Br, OR′, or N(R′)₂;    -   Ar₁ and Ar₂ are independently phenyl or Het with the proviso        that at least one Ar is Het;    -   Het is a heterocycle of from 5-6 atoms having from 1-4        heteroatoms or a fused heterocycle of from 9-10 atoms having 1-3        heteroatoms.

A compound which upon administering to a human being converts into acompound according to Formula I is within the scope of this invention.

Preferred compounds of Formula I are those wherein:

-   -   R₁ is isopropyl or t-butyl;    -   R₂ is H, methyl, or ethyl;    -   R₃ is H, (CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, (CR′₂)_(n)NR′COR,        (CR′₂)_(n)CO₂R, (CR′₂)_(n)OCOR, (CR′₂)_(n)CON(R)₂,        (CR′₂)_(n)OCON(R)₂, (CR′₂)_(n)NR′CON(R)₂, (CR′₂)_(n)NR′CO₂R,        (CR′₂)_(n)OSO₂N(R)₂, (CR′₂)_(n)NR′SO₂OR, (CR′₂)_(n)NR′SO₂N(R)₂,        (CR′₂)_(n)OSO₂R, (CR′₂)_(n)NR′SO₂R, (CR′₂)_(n)SO_(p)R,        (CR′₂)_(n)NR′CSN(R)₂, (CR′₂)_(n)COR, O(CR′₂)_(m)OR,        NR(CR′₂)_(m)OR, F, Cl, Br, CF₃, CN, or ═O;    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,        (CH₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,        (CR′₂)_(p)SO_(p)R, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,        (CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R,        (CR′₂)_(p)CON(R)₂, (CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂,        (CR′₂)_(p)NR′SO₂OR, (CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)Het and any        two of R₁-R₃ or R₄-R₆ may together form a ring of 5-6 total        atoms which may contain 0-2 heteroatoms;    -   n is an integer of 0 to 3;    -   m is an integer of 2 to 4;    -   p is 0 to 2;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing        1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may form a        heterocycle containing the nitrogen, all optionally substituted        by F, Cl, Br, OR′, N(R′)₂, NR′COR′, CF₃, or ═O—;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,        OR′, or N(R′)₂;    -   Ar₁ is phenyl or Het; and    -   Ar₂ is Het wherein Het is a heterocycle of from 5-6 atoms having        1-4 heteroatoms selected from: furan, pyrrole, thiophene,        oxazole, isoxazole, thiazole, pyrazole, 1,2,3-triazole,        1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine,        pyrazine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine,        piperazine, piperidine, morpholine, thiomorpholine, oxolane,        dioxane, sulfolane; or a fused heterocycle of from 9-10 atoms        having from 1-3 heteroatoms selected from: benzofuran, indole,        indoline, benzothiophene, benzimidazole, benzthiazole,        benzoxazole, quinoline, isoquinoline, cinnoline, quinazoline and        quinoxaline

Other preferred compounds of Formula I are those wherein:

-   -   R₁ is isopropyl or t-butyl;    -   R₂ is H, methyl or ethyl;    -   R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,        (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂,        (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,        (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R,        (CH₂)_(n)SO₂R, (CH₂)_(n)NR′CSN(R)₂, (CH₂)_(n)COR, O(CH₂)_(m)OR′,        NR(CH₂)_(m)OR′, or C(CH₃)₂OR′;    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,        (CH₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CH₂)_(p)NR′COR,        (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R,        (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,        (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2, or        R₄ and R₅ may together form a ring of 5-6 total atoms which may        contain 0-2 heteroatoms;    -   n is an integer of 0 to 3;    -   m is an integer of 2 to 4;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing        1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may be a        heterocycle containing the nitrogen, all optionally substituted        by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,        OR′, or N(R′)₂;    -   Ar₁ is phenyl; and    -   Ar₂ is a heterocycle of 5-6 atoms having from 1-4 heteroatoms        selected from: furan, pyrrole, thiophene, oxazole, isoxazole,        thiazole, pyrazole. 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,        tetrahydrothiophene, pyrrolidine, piperazine, piperidine,        morpholine, thiomorpholine, oxolane, dioxane, sulfolane; or a        fused heterocycle of 9-10 atoms having from 1-3 heteroatoms        selected from: benzofuran, indole, indoline, benzothiophene,        benzimidazole, benzthiazole, benzoxazole, quinoline,        isoquinoline, cinnoline, quinazoline and quinoxaline.

Still other preferred compounds of Formula I are those wherein:

-   -   R₁ is H, a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R₂ is H, a straight or branched alkyl of 1-5 carbons;    -   R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,        (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂,        (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,        (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R,        (CH₂)_(n)SO₂R, (CH₂)_(n)COR, O(CH₂)_(m)OR, NR(CH₂)_(m)OR,        C(CH₃)₂OR′, F, Cl, Br, CF₃, or ═O;    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,        (CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR,        (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R,        (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,        (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2;    -   R₄ and R₅ may together form a ring of 5-6 total atoms which may        contain 0-2 heteroatoms;    -   n is an integer of 0 to 3;    -   m is an integer of 2 to 4;    -   R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,        cyclopentyl or cyclohexyl;    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing        1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may be a        heterocycle containing the nitrogen, all optionally substituted        by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,        OR′, or N(R′)₂;    -   Ar₁ is phenyl or Het; and    -   Ar₂ is Het wherein Het is a heterocycle of 5-6 atoms having from        1-4 heteroatoms selected from: furan, pyrrole, thiophene,        oxazole, isoxazole, thiazole, pyrazole, 1,2,3-triazole,        1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine,        pyrazine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine,        piperazine, piperidine, morpholine, thiomorpholine, oxolane,        dioxane, sulfolane; or a fused heterocycle of from 9-10 atoms        having 1-3 heteroatoms selected from: benzofuran, indole,        indoline, benzothiophene, benzimidazole, benzthiazole,        benzoxazole, quinoline, isoquinoline, cinnoline, quinazoline and        quinoxaline.

Still other preferred compounds of Formula I are those wherein:

-   -   R₁ is H, methyl, ethyl, isopropyl, or t-butyl;    -   R₂ is H or methyl;    -   R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,        (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂,        (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,        (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R,        (CH₂)_(n)SO₂R, (CH₂)_(n)COR, O(CH₂)_(m)OR′, NR(CH₂)_(m)OR′,        C(CH₃)₂OR′, F, Cl, Br, CF₃, or ═O;    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,        (CH₂)_(n)N(R)₂, F, Cl, Br, CF₃, (CH₂)_(p)NR′COR,        (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R,        (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,        (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, (CH₂)_(p)Het wherein p is        0 to 2;    -   any two of R₄-R₆ may together form a ring of 5-6 total atoms        which may contain 0-2 heteroatoms;    -   n is an integer of 0 to 3;    -   m is an integer of 2 to 4;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from        1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may form a        heterocycle having nitrogen, all optionally substituted by F,        Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,        OR′, or N(R′)₂;    -   Ar₁ is a heterocycle of 5-6 atoms having from 1-4 heteroatoms        selected from: furan, pyrrole, thiophene, oxazole, isoxazole,        thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,        tetrahydrothiophene, pyrrolidine, piperazine, piperidine,        morpholine, thiomorpholine, oxolane, dioxane, sulfolane; or a        fused heterocycle of 9-10 atoms having 1-3 heteroatoms selected        from: benzofuran, indole, indoline, benzothiophene,        benzimidazole, benzthiazole, benzoxazole, quinoline,        isoquinoline, cinnoline, quinazoline and quinoxaline; and    -   Ar₂ is phenyl.

More preferred compounds of Formula I are those wherein:

-   -   R₁ is isopropyl or t-butyl;    -   R₂ is H or methyl;    -   R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)OCON(R)₂,        (CH₂)_(n)NR′CON(R)₂, (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂,        (CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)NR′SO₂R,        (CH₂)_(n)SO₂R, O(CH₂)_(m)OR′, NR(CH₂)_(m)OR′, or C(CH₃)₂OR′;    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CH₂)_(n)OR,        (CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR,        (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′COR,        (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,        (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2;    -   R₄ and R₅ may together form a ring of 5-6 total atoms which may        contain 0-2 heteroatoms;    -   n is an integer of 0 to 3;    -   m is an integer of 2 to 4;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from        1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may be a        heterocycle containing the nitrogen, all optionally substituted        by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,        OR′, or N(R′)₂;    -   Ar₁ is phenyl; and    -   Ar₂ is furan, pyrrole, thiophene, oxazole, isoxazole, thiazole,        pyrazole, tetrazole, or pyridine.

Other more preferred compounds of Formula I are those wherein:

-   -   R₁ is H, a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R₂ is H, methyl or ethyl or isopropyl;    -   R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NRCOR,        (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R)₂,        (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,        (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R,        (CH₂)_(n)SO₂R, O(CH₂)_(m)OR, NR(CH₂)_(m)OR′, C(CH₃)₂OR′, or ═O;    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR,        (CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR,        (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R,        (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,        (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2;    -   R₄ and R₅ may together form a ring of 5-6 total atoms which may        contain 0-2 heteroatoms;    -   n is an integer of 0 to 3;    -   m is an integer of 2 to 4;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms containing        1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may be a        heterocycle having nitrogen, all optionally substituted by F,        Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,        OR′, or N(R′)₂;    -   Ar₁ is thiophene, thiazole, pyridine, benzothiophene,        benzthiazole, benzoxazole, quinoline or isoquinoline; and    -   Ar₂ is phenyl or Het wherein Het is a heterocycle of 5-6 atoms        having from 1-4 heteroatoms selected from: furan, pyrrole,        thiophene, oxazole, isoxazole, thiazole, pyrazole,        1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine,        pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene,        pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine,        oxolane, dioxane, sulfolane; or a fused heterocycle of 9-10        atoms having 1-3 heteroatoms selected from: benzofuran, indole,        indoline, benzothiophene, benzimidazole, benzthiazole,        benzoxazole, quinoline, isoquinoline, cinnoline, quinazoline and        quinoxaline.

Still other more preferred compounds of formula IV are those wherein:

-   -   R₁ is isopropyl or t-butyl;    -   R₂ is H, methyl, or ethyl;    -   R₃ is CH₂OH, NH₂, OCH₂CH₂OH, NHCOR, OSO₂N(R)₂, NR′SO₂OR,        NR′SO₂R, or OSO₂R;    -   R₄, R₅ and R₆ are independently H a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR,        (CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR,        (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R,        (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,        (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0 to 2;    -   R₄ and R₅ may together form a ring of 5-6 total atoms which may        contain 0-2 heteroatoms;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons,    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from        1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may be a        heterocycle having nitrogen, all optionally substituted by F,        Cl, Br, OR′, N(R′)₂, NR′COR′, or ═O;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of from 1-4 carbons, F,        Cl, Br, OR′, or N(R′)₂;    -   Ar₁ is phenyl; and    -   Ar₂ is a heterocycle of 5-6 atoms having from 1-4 heteroatoms        selected from: furan, pyrrole, thiophene, oxazole, isoxazole,        thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,        tetrahydrothiophene, pyrrolidine, piperazine, piperidine,        morpholine, thiomorpholine, oxolane, dioxane, sulfolane; or a        fused heterocycle of 9-10 atoms having from 1-3 heteroatoms        selected from: benzofuran, indole, indoline, benzothiophene,        benzimidazole, benzthiazole, benzoxazole, quinoline,        isoquinoline, cinnoline, quinazoline and quinoxaline.

Still other more preferred compounds of Formula I are those wherein;

-   -   R₁ is H, methyl, ethyl, isopropyl, or t-butyl;    -   R₂ is H or methyl;    -   R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR,        (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂, (CH₂)_(n)NR′CON(R),        (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂, (CH₂)_(n)NR′SO₂OR,        (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R, (CH₂)_(n)NR′SO₂R,        (CH₂)_(n)SO₂R, (CH₂)_(n)NR′CSN(R)₂, (CH₂)_(n)COR, O(CH₂)_(m)OR,        NR(CH₂)_(m)OR′, C(CH₃)₂OR′, F, Cl, Br, or ═O;    -   R₄, R₅ and R₆ are independently H, methyl, ethyl, OH, CH₂OH,        CH₂CH₂OH, F, Cl, NH₂;    -   any two R₄-R₆ may form a ring of 5-6 atoms having from 1-2        heteroatoms;    -   n is an integer of 0 to 3;    -   m is an integer of 2 to 4;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons;    -   R is H, a straight or branched alkyl of 1-4 carbons,        (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms having from        1-2 heteroatoms or a heterocycle having a nitrogen, all        optionally substituted by F, Cl, Br, OR′, N(R′)₂, NR′COR′, or        ═O;    -   R′ is H, a straight or branched alkyl of 1-4 carbons, or phenyl;    -   R″ is H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,        OR′, or N(R′)₂;    -   Ar₁ is furan, thiophene, thiazole, pyridine, imidazole,        benzofuran, benzothiophene, benzimidazole, benzthiazole,        quinoline, or isoquinoline; and    -   Ar₂ is phenyl.

Still other more preferred compounds of formula IV are those wherein:

-   -   R₁ is H, methyl, ethyl, isopropyl, or t-butyl;    -   R₂ is H or methyl;    -   R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, or ═O;    -   R₄, R₅, and R₆ are independently H, methyl, OH, CH₂OH, CH₂CH₂OH,        NH₂, or F;    -   R₇ is H, isopropyl, butyl, sec-butyl, cyclobutyl, cyclopentyl,        or cyclohexyl;    -   R is H, methyl, ethyl, phenyl, or CH₂Ph and wherein the (R)₂ of        N(R)₂ may be a heterocycle having a nitrogen;    -   R″ is H, F, or CH₃;    -   Ar₁ is furan, thiophene, thiazole, pyridine, imidazole,        benzofuran, benzothiophene, benzimidazole, benzthiazole,        quinoline, or isoquinoline; and    -   Ar₂ is phenyl.

Most preferred compounds of Formula I are those wherein:

-   -   R₁ is H, methyl, ethyl, isopropyl, or t-butyl;    -   R₂ is H, methyl, ethyl, or isopropyl;    -   R₃ is H, NH₂, OH, CH₂OR, CH₂N(R)₂, CH₂CON(R)₂, CH₂OSO₂N(R)₂,        CH₂NHSO₂OR, CH₂NHSO₂R, CH₂OSO₂R, Cl, Br, or OCH₂CH₂OH;    -   R₄, R₅, and R₆ are independently H, methyl, ethyl, isopropyl,        OH, NH₂, CH₂OR, CH₂N(R)₂, ═O, F, Cl, Br, or CH₂NRCOR;    -   R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or        cyclopentyl;    -   R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂        may be a heterocycle having a nitrogen;    -   R″ is H, F, or CH₃;    -   Ar₁ is thiophene, thiazole, furan, pyridine, benzothiophene,        benzofuran, benzthiazole, benzoxazole, quinoline, or        isoquinoline; and    -   AR₂ is furan, thiophene, oxazole, isoxazole, imidazale,        thiazole, pyrazole, pyridine, benzofuran, benzothiophene,        benzimidazole, benzthiazole, quinoline, or isoquinoline.

Other most preferred compounds of Formula I are those wherein:

-   -   R₁ is isopropyl or t-butyl;    -   R₂ is H, methyl, or ethyl;    -   R₃ is H, NH₂, OH, CH₂OR, CH₂N(R)₂, CH₂CON(R)₂, OSO₂N(R)₂,        NHSO₂OR, NHSO₂R, OSO₂R, or OCH₂CH₂OH;    -   R₄, R₅, and R₆ are independently H, methyl, ethyl, isopropyl,        OH, NH₂ CH₂OR; CH₂N(R)₂, ═O, F, Cl, Br, or CH₂NRCOR;    -   R₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or        cyclopentyl;    -   R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂        may be a heterocycle containing the nitrogen;    -   R″ is H, F, or CH₃;    -   Ar₁ is phenyl; and    -   Ar₂ is furan, thiophene, oxazole, isoxazole, imidazale,        thiazole, pyrazole, pyridine, benzofuran, benzothiophene,        benzimidazole, benzthiazole, quinoline, or isoquinoline.

Still other most preferred compounds of Formula I are those wherein:

-   -   R₁ is isopropyl or t-butyl;    -   R₂ is H, methyl, or ethyl;    -   R₃ is NH₂, CH₂OH, OCH₂CH₂OH, or CH₂CH₂OH;    -   R₄, R₅, and R₆ are independently H, NH₂, CH₂OH, ═O, methyl,        ethyl, or isopropyl;    -   R₇ is isopropyl;    -   R″ is H, F, or CH₃;    -   Ar₁ is phenyl; and    -   Ar₂ is furan, thiophene, imidazole, thiazole, pyrazole, or        pyridine.

Still other most preferred compounds of Formula I are those wherein:

-   -   R₁ is H, methyl, ethyl, isopropyl, or t-butyl;    -   R₂ is H or methyl;    -   R₃ is H, CH₂OH, NH₂, or ═O;    -   R₄, R₅, and R₆ are independently H, OH, CH₂OH, NH₂, or F;    -   R₇ is isopropyl, sec-butyl, isobutyl, or cyclopentyl;    -   R is H, methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂        may be a heterocycle having a nitrogen;    -   R″ is H, F, or CH₃;    -   Ar₁ is furan, thiophene, imidazole, thiazole, pyrazole, or        pyridine; and    -   Ar₂ is phenyl.

Especially preferred compounds of the invention are:

-   -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;    -   6-[-2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;    -   3-(2-Amino-5-isopropyl-benzothiazol-6-yl-sulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-phenethyl-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   (S)-(6-{4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-isopropyl-7-methyl-benzothiazol-2-yl)-carbamic        acid methyl ester;    -   (S)-3-(2-Amino-6-tert-butyl-benzothiazol-4-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(3-tert-Butyl-benzo[b]thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-benzo[b]thiophen-2-yl-sulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   4-Hydroxy-3-(5-hydroxymethyl-2-isopropyl-thiophen-3-ylsulfanyl)-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-thiazol-2-yl)-acetamide;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxy-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydrox-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   6-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(2-amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   (S)-4-Hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-6-phenethyl-5,6-dihydro-pyran-2-one;    -   (S)-4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;    -   3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   (R)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-[2-tert-Butyl-4-(2-hydroxy-ethyl)-5-methyl-phenylsulfanyl]-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   5-Trifluoromethyl-pyridine-2-sulfonic acid        {5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;        and    -   5-Trifluoromethyl-pyridine-2-sulfonic acid        {5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide.

Other preferred compounds are:

-   -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-furan-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   6-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(2-Amino-thiazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-oxazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(1H-benzoimidazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(1H-Benzoimidazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(3-Amino-1H-indazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-4-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(3-Amino-1H-indazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(5-tert-Butyl-2-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-tert-Butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-tert-Butyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(4-Amino-phenyl)-ethyl]-3-(2-tert-butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(4-Amino-phenyl)-ethyl]-3-(4-tert-butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(4-Amino-phenyl)-ethyl]-3-(3-tert-butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one,    -   3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;    -   N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;    -   N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;    -   N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;    -   3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-acetamide;    -   N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-methanesulfonamide;    -   3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;        and compounds useful as intermediates in the preparation of the        final products are:    -   a compound of Formula IA        wherein    -   R₄, R₅, and R₆ are independently H, a straight or branched alkyl        of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CR′₂)_(n)OR,        (CR′₂)_(n)N(R)₂, F, Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR,        (CR′₂)_(p)SO_(p)R, (CR′₂)_(p)R, (CR′₂)_(p)OCOR, O(CR′₂)_(m)OR,        NR(CR′₂)_(m)OR, (CR′₂)_(p)NR′CON(R)₂, (CR′₂)_(p)OCON(R)₂,        (CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R,        (CR′₂)_(p)CON(R)₂, (CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂,        (CR′₂)_(p)NR′SO₂OR, (CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)NR′SO₂N(R)₂,        (CR′₂)_(p)C(NR′)N(R)₂, (CR′₂)_(p)NR′C(NR′)N(R)₂, (CR′₂)_(p)Het;    -   any two of R₄-R₆ may together form a ring of 5-6 total atoms        which may contain 0-3 heteroatoms;    -   n is an integer of from 0 to 3;    -   p is an integer from 0 to 2;    -   R₇ is a straight or branched alkyl of 1-6 carbons or a        carbocycle of 3-6 carbons.    -   R is independently H, a straight or branched alkyl of 1-4        carbons, (CH₂)_(n)Ph, or a (CH₂)_(n)heterocycle of 5-6 atoms        containing 1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may        form a heterocycle containing the nitrogen, all optionally        substituted by F, Cl, Br, OR′, CN, CO₂R′, N(R′)₂, NR′COR′, CF₃,        or ═O;    -   R′ is independently H, a straight or branched alkyl of 1-4        carbons, or phenyl;    -   R″ is independently H, a straight or branched alkyl of 1-4        carbons, F, Cl, Br, OR′, or N(R′)₂;    -   Ar₂ is phenyl or Het wherein Het is a heterocycle of from 5-6        atoms having from 1-4 heteroatoms.

Terms useful in describing the instant invention are as follows:

The term “alkyl” means a straight or branched hydrocarbon radical havingfrom 1 to 12 carbon atoms unless otherwise specified and includes, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, undecyl, and dodecyl. The alkyl groups may contain one or moresites of unsaturation such as double or triple carbon-carbon bonds. Thealkyl group is unsubstituted or substituted by from 1 to 3 substituentsselected from F, Cl, Br, OH, NH₂, CN, NO₂, OCH₃, OCH₂CH₂OH, NHCH₃, orN(CH₃)₂.

The term “cycloalkyl” means a hydrocarbon ring which contains from 3 to12 carbon atoms unless otherwise specified, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Where possible, thecycloalkyl group may contain double bonds. The cycloalkyl ring may beunsubstituted or substituted by from 1 to 3 substituents selected fromalkyl, alkoxy, thioalkoxy all as defined herein, hydroxy, thiol, nitro,halogen, amino, formyl, carboxyl, nitrile, —NH—CO—R, —CO—NHR—, —CO₂R,—COR, aryl, or heteroaryl wherein alkyl (R), aryl, and heteroaryl aredefined as herein.

The term “carbocycle” means cycloalkyl as defined above.

The term “heteroatoms” means a nitrogen, sulfur, or oxygen.

The term “heterocycle” means a heterocyclic radical which are 5-6 atomshaving 1-4 heteroatoms and selected from 1-4 heteroatoms selected from:furan, pyrrole, thiophene, oxazole, isoxazole, thiazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine,piperazine, piperidine, morpholine, thiomorpholine, oxolane, dioxane,sulfolane, unsubstituted or substituted by 1 to 2 substituents selectedfrom alkyl as defined above. For heterocycles containing sulfur, theoxidized sulfur heterocycles containing SO or SO₂ groups are alsoincluded.

The term “fused heterocycle” refers to a heterocycle that is adjoined astwo consecutive positions with a phenyl ring or another heterocycle,such rings may include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-,4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl,2-, 3-, 4-, 5-, 6-, or 7-indolinyl, 2-, 3-, 4-, 5-, 6-, or7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl,

-   -   2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or        7-benzothiazolyl.

For purposes of the syntheses of the compounds of the present invention,reactive functional groups present in starting materials, reactionintermediates, or reaction products may be protected during chemicalreactions using protecting groups which render the reactive functionalgroups substantially inert to the reaction conditions (see for example,Protective Groups in Organic Synthesis, 2nd ed., T. W. Green and P. G.Wuts, John Wiley & Sons, New York, N.Y. 1991). Thus, for example,protecting groups such as the following may be utilized to protectsuitable amino, hydroxyl, and other groups of related reactivity:carboxylic acyl groups, such as formyl, acetyl, trifluoroacetyl;alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl (BOC),β,β,β-trichloroethoxycarbonyl (TCEC), β-iodoethoxycarbonyl;aryloxycarbonyl groups, such as benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl groups, suchas trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such astrityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl,diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be utilized.The protecting group may be removed, after completion of the syntheticreaction of interest, by procedures known to those skilled in the art.For example, a BOC group may be removed by acidolysis, a trityl group byhydrogenolysis, TBDMS by treatment with fluoride ions, and TCEC bytreatment with zinc.

Some of the compounds of Formula I are capable of further formingpharmaceutically acceptable acid-addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihyrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinates suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977;66:1-19.

The acid addition salt of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge, supra., 1977).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.Configuration drawn is most preferred.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted, and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or, synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as antagonists of a retroviral protease, as agentsfor the treatment of infections caused by a retrovirus including HIV, oras agents for the treatment of diseases due to AIDS, the compoundsutilized in the pharmaceutical method of this invention are administeredat the initial dosage of about 0.01 mg to about 100 mg/kg daily. A dailydose range of about 0.01 mg to about 10 mg/kg is preferred. The dosages,however, may be varied depending upon the requirements of the patient,the severity of the condition being treated, the compound beingemployed. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

The compounds of the instant invention, protease inhibitors, can be usedas a component of initial patient antiretroviral therapy for HIV as, forexample, in the following regimen:

-   -   Choose one combination of nucleoside reverse transcriptase        inhibitors    -   Zidovudine+lamivudine    -   Zidovudine+didanosine    -   Zidovudine+zalcitabine    -   Didanosine+stavudine    -   Didanosine+lamivudine    -   Stavudine+lamivudine    -   Abacavir+zidovudine+lamivudine

AND one of the compounds of the instant invention.

In addition, one may use one of the nucleoside reverse transcriptaseinhibitor combinations above with one of the agents below plus acompound of the instant invention.

-   -   Nelfinavir    -   Indinavir    -   Saquinavir (soft gel-cap now preferred over hard gel-cap)    -   Ritonavir    -   Nevirapine    -   Delavirdine    -   Efavirenz

The compounds of the instant invention can be used in multiplecombinations with available antiretroviral drugs for combinationtherapy. The following are illustrative:

Drug class/agents Dosage Nucleoside reverse transcriptase inhibitorsAbacavir 300 mg bid Didanosine 200 mg bid (for patients <60 kg, 125 mgbid) Lamivudine 150 mg bid (for patients <50 kg, 2 mg/kg bid) Stavudine40 mg bid (for patients <60 kg, 30 mg/kg bid) Zalcitabine 0.75 mg tidZidovudine 300 mg bid Non-nucleoside reverse transcriptase inhibitorsDelavirdine 400 mg tid Efavirenz 600 mg qd Nevirapine 200 mg bidProtease inhibitors Indinavir 800 mg q8h Nelfinavir 750 mg tid Ritonavir600 mg bid Saquinavir 600 mg tid (hard gel-cap formulation), 1200 mg tid(soft gel-cap formulation)

The compounds of the instant invention can be used with or instead ofthe following for the treatment of established HIV infection.

Preferred Strong evidence of clinical benefit and/or sustainedsuppression of plasma viral load. One choice each from column A andcolumn B. Drugs are listed in random, not priority, order: Column AColumn B Indinavir (AI) ZDV + ddl (AI) Nelfinavir (AII) d4T + ddl (AII)Ritonavir (AI) ZDV + ddC (AI) Saquinavir − SGC (AII) ZDV + 3TC (AI)Ritonavir + Saquinavir SGC or HGC d4T + 3TC (AII) (BII) Efavirenz (AII)Alternative Less likely to provide sustained virus suppression, or datainadequate. Nevirapine or delavirdine + two NRTIs (Column B, above)(BII)

The compounds of the instant invention can be used with the followingdrugs available through treatment investigational new drug protocols.

Amprenavir Adefovir Abacavir (Agenerase; Drug (Preveon) (1592-U89)141W94) Source Gilead Glaxo-Wellcome Vertex; 800-GILEAD-5 800-501-4672Glaxo-Wellcome 800-248-9757 Class Nucleotide RT Nucleoside RT ProteaseInhibitor Inhibitor Inhibitor Usual 60 mg po qd or 300 mg po bid 1200 mgpo bid dose 120 mg po qd + L-carnitine 500 mg po qd Side Proximal renaltubular Hypersensitivity: Nausea, diarrhea, effects dysfunction, nausea,2-5% usually in rash, headache (major) elevated LFTs first 4 weeks(fever, nausea, vomiting, morbilliform rash)

The compounds of the present invention can be prepared according to thevarious synthetic schemes that follow. Protecting groups may be usedwhen appropriate throughout many of the schemes. Although specificallynoted in certain schemes, the appropriate use and choice of protectinggroups is well-known by one skilled in the art, and is not limited tothe specific examples below. It is also understood that such groups notonly serve to protect chemically reactive sites, but also to enhancesolubility or otherwise change physical properties. A good generalreference for protecting group preparation and deprotection is“Protecting Groups in Organic Synthesis” by Theodora Green. A number ofgeneral reactions such as oxidations and reductions are not shown indetail but can be done by methods understood by one skilled in the art.General transformations are well-reviewed in “Comprehensive OrganicTransformation” by Richard Larock, and the series “Compendium of OrganicSynthetic Methods” published by Wiley-Interscience. In general, thestarting materials were obtained from commercial sources unlessotherwise indicated.

There are three major components of the synthesis of the desiredproducts: the formation of a ketone precursor; the cyclization of thatketone into the dihydropyrone ring system; and the addition of the thiolcomponent to complete the preparation of the compounds of the invention.Schemes 1 through 6 address the various methods for preparation ofketones indicated as C, D, G, and K.

Aldehyde Synthesis

The desired aldehydes which can be used in Schemes 2 and 3 are preparedby a number of methods as indicated in Scheme 1. The appropriate estercan be reduced to the corresponding alcohols and then oxidized to thealdehyde. Another method involves preparation of an anion with anappropriate base and trapping with a reagent, such as DMF, to preparethe aldehyde.

The desired ketones can be prepared as shown in Schemes 2 and 3. Theappropriate alpha halo ketone can be displaced with triphenylarsine toprepare an arsenate reagent. In a similar manner, triphenylphosphine canbe used to prepare a Wittig reagent which will also carry out thereaction shown in Scheme 2. Upon treating the arsenate reagent and thealdehyde with base such as potassium carbonate, the chalcone derivativeC is formed. Compound C can then be reduced using hydrogen with anappropriate catalyst to prepare ketone D.

Alternatively, the desired enones C can be prepared by reaction of theappropriate methylketones and aldehydes using Ba(OH)₂ in EtOH asdescribed in Synthesis, 1983:502-504, An. Quim, Ser. C,1981;77(2):222-294, and Pol. J. Chem., 1982;56(10-112):1435. In asimilar fashion, the enones C can also be prepared by reaction of theappropriate methylketones and aldehydes using NaOH in EtOH as describedby Kohler and Chadwell, Org. Synth. Coll., 1941;1:78. The relative ratioof aldehyde, ketone, base, and temperature (RT to reflux) variedaccording to the substitution pattern of the aldehyde and ketone. Therehave also been reports of conversion of A and B to chalcones C underacidic conditions using H₂SO₄ and acetic anhydride. This may beaccomplished by direct treatment with acid or the acid may be used todehydrate the aldol intermediate if it does not dehydrate during thereaction with base.

The resulting chalcones C were converted into ketones D by reduction asnoted previously in Scheme 2. The reduction was generally accomplishedby hydrogenation using palladium on barium sulfate at room temperaturein tetrahydrofuran. On occasion, overreduction to the alcohol wasobserved. The isolated alcohol or the crude mixture can be oxidized tothe ketone with Jones reagent.

The reduction of the enone to the corresponding ketone can be carriedout via a number of alternative methods including but not limited to:metals in ammonia as described in Org. Reactions, 1976;23:1-253;ethylene glycol and RuCl₂[P(Ph)₃]₃ as described in Synthesis, 1973:359:and copper hydride reagents as described in J. Amer. Chem. Soc.,1974;96:3686.

Preparation of the ketone G can be accomplished from an appropriateacid(E) and appropriate nucleophile using the Weinreb methodologydescribed in Tetrahedron Letters, 1987:1857. The appropriate acid can beconverted to the acid chloride by treatment with neat thionyl chlorideor by treatment with oxalyl chloride in methylene chloride with acatalytic amount of DMF. Treatment of the acid chloride withN,O-dimethylhydroxylamine with bases such as pyridine or triethylaminein inert solvents such as methylene chloride from 0° C. to reflux willgive intermediate F. Intermediate F can then be converted to G bytreatment with the appropriate nucleophile, such as Grignard reagents,at 0° C. to reflux in solvents such as tetrahydrofuran or ether. Analternative method of converting the acid E to ketone G is by treatmentwith alkyl lithiums at −78° C. to reflux as described in J. Med. Chem.,1996;39:2659 and J. Amer. Chem., Soc. 1970;92:2590. Another route istreatment of the acid chloride with nucleophiles (organomagnesium,copper, cadmium, or zinc reagents) as reviewed in Org. React., 1954;8:28and Tetrahedron Lett., 1970:4647.

An alternative preparation of ketone D can be accomplished by reactionof an allylic alcohol I with an appropriate halide H using palladiumacetate as described in Tetrahedron, 1979;35:329 and Tetrahedron Lett.,1991;32:2121.

There are a number of catalysts and conditions which will effect thistransformation such as: Pd(OAc)₂, NaHCO₃, DMF, tetrabutylammoniumchloride at room temperature to reflux; Pd(OAc)₂, triethylamine,acetonitrile at room temperature to reflux. The desired ketone D canalso be prepared by acid catalyzed reaction of allylic alcohol 1, or anenone, with an appropriate heterocycles as described in Heterocycles,1987;25:399.

An alternate preparation of ketone G can be accomplished by reaction ofaldehyde A with an appropriate nucleophile such as an organo lithium orGrignard reagents from −78° C. to room temperature in inert solvents toafford the alcohol. The desired ketone G can by formed by oxidation ofthe resulting alcohol with Jones reagent or other oxidizing conditionssuch as the Swern oxidation which are well-known to one skilled in theart.

Acid E can be converted to desired ketone K utilizing a four step routeindicated in Scheme 7. The appropriate acid E can be converted into thecorresponding β-ketoester J utilizing conditions described inTetrahedron Letters, 1992:1945 and Angew. Chem. Int. Ed. 1979:72. Theresulting β-ketoester L can be treated with a base, such as NaH orlithium diisopropylamide (LDA), then with an appropriate alkylatingagent, R′X at 0° C. to room temperature to give the alkylatedβ-ketoester. The β-ketoester can be decarboxylated with acid intetrahydrofuran at reflux. Alternatively the β-ketoester can behydrolyzed with base to the acid, then heated with or without acid togive the desired ketone K.

The ketones C, D, G, and K and those prepared from Scheme 7 are cyclizedto the dihydropyrone ring following the routes shown in Schemes 8 and 9.Scheme 9 also describes methods for obtaining optically pure forms ofthe dihydropyrone ring which is a recognized and important aspect of thecurrent invention. The same methods can be used to produce racemiccompounds if the resolution step is removed.

The dihydropyrone ring system can be prepared as described in Can. J.Chem., 1974;52:2157-2164 and Synthetic Communications, 1988;18(9):949-963. Reaction of the dianion of acetoacetate (L) with theappropriate ketone (C, D, G, or K) in inert solvents such astetrahydrofuran at 0° C. to room temperature gave aldol intermediate M.H₂O can be added directly to the reaction to effect closure.Alternatively the reaction can be worked up by addition of acetic acidor ammonium chloride and the aldol product isolated and characterized ortaken on crude. The aldol product M can be closed by treating withdilute sodium hydroxide with or without tetrahydrofuran present. Thetetrahydrofuran may be necessary to assist in solubilizing the aldolintermediate M. Protecting groups on intermediate M can be removedbefore closure to assist in solubilizing the intermediate in base.

Other routes are available to form the dihydropyrone ring such as thosedescribed in: J. C. S. Chem. Comm., 1979:578; J. Am. Chem. Soc., 1984;106:4294; and J. Org. Chem., 1975;40:1610.

The dihydropyrone ring system can also be prepared optically enriched asshown in Scheme 9. The appropriate ketone (C, D, G, or K) can be reactedwith the appropriate Reformatsky reagent or the equivalent lanthamidespecies (Tetrahedron, 1981;37(Supp. 1):175; J. Org. Chem., 1984;49:3904)in inert solvents such as tetrahydrofuran at −78° C. to reflux to affordthe aldol intermediate. The two antipodes can be separated by a chiralHPLC column such as Chiralcel OD (90% hexane:0.1% TFA:10% isopropylalcohol) or selective enzymatic hydrolysis with enzymes such as Candidaantarctica “B” lipase in phosphate buffer with co-solvents such asisopropyl alcohol at room temperature. The resolved ester can behydrolyzed to the acid O* using base under standard conditions.

Intermediate R* can also be prepared in a chiral form by reaction ofketone C, D, G or K with a chiral ester Q to give an intermediate whichis a mixture of diastereomers (J. Org. Chem., 1982;47:91; Tetrahedron,1980;36:227). The aldol mixture can be separated by recrystallization orby chromatography to give each enantiomer. Hydrolysis of the ester usingbase affords acid R*.

Intermediate O can be prepared in racemic form and then resolved byclassical means such as co-crystallization with a chiral amine such as1-(1-naphthyl)ethylamine in solvents such as H₂O. Analysis of the chiralsalt by x-ray may allow the determination of the absolutestereochemistry of intermediate O*.

The intermediates O* or R* can be converted to P* by activation of theacid and treatment with the magnesium salt of a half acid ester. ThenP*, like M, may be converted to N or N* by base.

Schemes 10 to 14 describe the synthesis of a number of the tosylreagents (X, BB, HH) which are used to introduce the 3-thiol moiety tothe dihydropyrones of the invention.

Phenol S can be reacted with electrophiles, such as HC(OEt)₃ in inertsolvents with a Lewis acid, to give the para-substituted phenol. Thephenol can be protected with groups such as methoxyethoxymethyl ortertbutyldimethylsilyl which are known to one skilled in the art. Thederivatized phenol can be converted to the corresponding thiol using avariety of methods (Tetrahedron Lett., 1996:4523; Chem. Lett., 1985:1307and Tetrahedron Lett., 1993 :393). The Newman-Kwart rearrangement isalso useful for the conversion of phenol to thiophenol as described inJ. Org. Chem., 1966:3980; Synth., 1975:43; and J. Chem. Eng. Data,1975;20:443. Phenol U can be treated with bases such as sodium hydrideand dimethylthiocarbamoyl chloride in solvents such as DMF ortetrahydrofuran at 0° C. to reflux to give V. Vigorous heating of V attemperatures in the 200° C. to 330° C. range affords intermediate X. Thefree thiol can be prepared by reduction of derivatives such as W withdiisobutylaluminum hydride (DIBAL-H) or sodium borohydride in inertsolvents such as toluene or tetrahydrofuran from −78° C. to roomtemperature or by hydrolysis in base. The desired thiotosylate X can beprepared by reaction of the thiol with tosyl bromide and base such astriethylamine or pyridine in inert solvents such as carbon tetrachlorideat 0° C. to room temperature.

Another route into desired thiotosyl reagents is indicated in Scheme 11.Aniline Y can be converted to the corresponding phenol using a varietyof conditions (J. Org. Chem., 1951;16:586; Org. Synth., 1955;Coll. Vol.3:130). The phenol can be treated with sodium thiocyanate, sodiumbromide, and bromine in MeOH at 0° C. to 50° C. to incorporate thethiocyanate to give Z (Synth., 1992:656). The phenol can be modified orprotected using conditions which are understood by one skilled in theart. The thiocyanate can be converted to the thiol (AA) by treatmentwith dithiothreitol (DTT) in phosphate buffer in ethanol at roomtemperature to reflux or by treatment with lithium aluminum hydride(LAH) in inert solvents such as tetrahydrofuran at 0° C. to roomtemperature. The desired thiotosylate BB can be prepared by reaction ofthe thiol with tosyl bromide and base as described in Scheme 10.

Thiol AA can be converted to the disulfide (CC) by treatment with iodineand triethylamine in EtOAc. The disulfide can act as a protecting groupfor the sulfur. Various reactions can then be carried out on CC and thedisulfide converted back to the thiol by treatment with dithiothreitol(DTT) using similar conditions as described in Scheme 11. Reaction ofthe free thiophenol with tosyl bromide as previously described affordsthe desired tosyl reagent BB.

Thiocyanate Z can be converted to the thiol and then to thiotosylate DDusing conditions which have been described in previous schemes.Thiotosylate DD can be derivatized or a protecting group attached usingconditions known to one skilled in the art to give BB.

The nitro aromatic EE (J. Org. Chem., 1951:586) can be reduced to thecorresponding aniline by hydrogenation over Raney Nickel at roomtemperature. The thiocyanate can be introduced para to the amine in asimilar manner as described in Scheme 11. Aniline FF can be converted toGG by modification of the amine, conversion to thiol, and tosylation aspreviously described. Alternatively aniline II can be protected,converted to the thiol, and reacted with tosyl bromide to give JJ.Aniline JJ can be deprotected and then modified to give HH. Thereactions in this scheme have been previously described or are known toone skilled in the art.

Scheme 15 shows the convergent preparation of the desired compounds ofthe invention. The dihydropyrones (N) described in Schemes 8 and 9 arereacted with the tosyl reagents (X, BB, HH) described in Schemes 10 to14 to produce the target compounds.

The desired dihydropyrone KK can be prepared by reaction with theappropriate dihydropyrone N or N*, thiotosylate (X, BB, HH), andpotassium carbonate in dimethylformamide (DMF) at room temperature.Other bases and solvents will also effect this reaction such astriethylamine in ethanol or sodium hydride in tetrahydrofuran at 0° C.to reflux. Alternatively, the intermediate N can be brominated with NBSin tert-butanol and then displaced with the thiols such as AA and GG.

Scheme 16 describes alternative methods for effecting the separation ofenantiomers into optically pure forms after formation of thedihydropyrone ring.

It has been shown that tetrahydropyrones can be resolved as described inthe ICI patent WO 93/06235. The 4-hydroxydihydropyrone can be convertedto a ester and the ester hydrolyzed with an enzyme to afford chiralmaterial. This or other similar enzymatic processes may be applicable tothe dihydropyrones as indicated in Scheme 16. The 4-hydroxydihydropyronemay also be resolved by classical means by conversion into a salt withchiral amines such as 1-(1-naphthyl)ethylamine. The salt may berecrystallized and then freed to afford the desired chiral material MM*.

Scheme 17 shows the general preparation of a number of substitutedheterocycles. When X is a halogen, a metal halogen exchange can bepreformed to prepare the appropriate anion which can be trapped with anappropriate electrophile (E). This can be used to prepare heterocyclicaldehydes by trapping with DMF, thiols by trapping with sulfur, andalkyl groups by trapping with alkyl ketones or alkyl halides. In certaincases an appropriate base will deprotonate a heterocyclic hydrogen toprepare an anion directly. The following references exemplify Scheme 17:J. Chem. Soc., Perkin Trans. 1, 1997:3465; J. Chem. Soc., Perkin Trans.1, 1995:2913; J. Org. Chem., 1971;36(18):2690.

Preparation of Aldehydes

EXAMPLE A-1

5-Methyl-thiazole-4-carbaldehyde

A solution of 2.48 g (14.4 mmol) of 5-methyl-thiazole-4-carboxylic acidethyl ester (J. Chem. Soc., Perkin Trans. 1, 1982:159-164) indichloromethane (CH₂Cl₂) (50 mL) was cooled to −78° C. under nitrogen.DIBAL (Diisobutylaluminum hydride) (1.0 M in CH₂Cl₂, 15 mmol) was addeddropwise, and the solution was stirred at low temperature for 45minutes. Another 10 mmol of DIBAL was then added dropwise, and themixture was stirred for another 45 minutes. A solution of methanol(MeOH):acetic acid (10 mL:5 mL) was added slowly, followed by H₂O. Theorganic layer was separated, washed with brine, and dried (MgSO₄).Concentration gave a residue which was chromatographed on silica gel,eluting with 2:1 hexane:ethyl acetate (EtOAc), to give the titlecompound.

¹H NMR (CDCl₃): δ 2.76 (s, 3H), 8.58 (s, 1H), 10.14 (s, 1H).

EXAMPLE A-2

2-Methyl-thiazole-4-carbaldehyde

A mixture of 5.52 g (30 mmol) of 4-chloromethyl-2-methylthiazolehydrochloride and 0.5 M NaOH (180 mL) was refluxed for 8 hours and thenstirred for 18 hours at room temperature. EtOAc and H₂O were added. Theorganic phase was separated, washed with brine, and dried (MgSO₄).Concentration gave 4-(hydroxymethyl)-2-methylthiazole.

¹H NMR (CDCl₃): δ 2.63 (s, 3H), 4.66 (s, 2H), 6.96 (s, 1H).

The crude product (2.2 g, 17 mmol) was oxidized with MnO₂ (20 g) in 75mL of CHCl₃ for 16 hours. The suspension was filtered, and the filtratewas concentrated. The residue was chromatographed on silica gel, elutingwith 2:1 hexane:EtOAc, to give the title compound.

¹H NMR (CDCl₃): δ 2.71 (s, 3H), 7.98 (s, 1H), 9.89 (s, 1H).

EXAMPLE A-3

2-iso-Propyl-thiazole-4-carbaldehyde

A solution of 2.7 g (13 mmol) of 2-isopropyl-thiazole-4-carboxylic acidethyl ester (J. Med. Chem., 1998:602-617) in CH₂Cl₂ (50 mL) was cooledto −78° C. under nitrogen and treated dropwise with DIBAL (15 mL of 1.0M in CH₂Cl₂; 15 mmol). The mixture was stirred at low temperature for 45minutes and then treated with another 15 mL of DIBAL. The solution wasstirred for 1 hour at −78° C. Five percent citric acid was added, andthe mixture was extracted with EtOAc (3×100 mL). The combined extractswere washed with brine, dried (MgSO₄), and concentrated. Chromatographyof the residue over silica gel, eluting with 3:1 hexane:EtOAc, gave thetitle compound.

¹H NMR (CDCl₃): δ 1.37 (d, 6H), 3.30-3.35 (m, 1H), 8.01 (s, 1H), 9.93(s, 1H).

EXAMPLE A-4

4-iso-Propyl-thiazole-5-carbaldehyde

A solution of 5.9 g (30 mmol) of 4-isopropyl-thiazole-5-carboxylic acidethyl ester (J. Chem. Soc., Perkin Trans. 1, 1982:159-164) in toluene(100 mL) was cooled in an ice bath under nitrogen and treated dropwisewith DIBAL (150 mL of 1.0 M; 150 mmol). The mixture was stirred at lowtemperature for 45 minutes and then allowed to warm to room temperatureovernight. H₂O was added cautiously, and the mixture was extracted withEtOAc (3×200 mL). The combined extracts were washed with brine, dried(MgSO₄), and concentrated. The crude5-(hydroxymethyl)-4-isopropyl-thiazole thus obtained was used as is inthe next step.

¹H NMR (CDCl₃): δ 1.30 (d, 6H), 3.13-3.20 (m, 1H), 4.85 (s, 2H), 8.67(s, 1H).

A mixture of 4.65 g (30 mmol) of crude5-(hydroxymethyl)-4-isopropyl-thiazole in 200 mL of chloroform (CHCl₃)was treated with 45 g of MnO₂ and stirred at room temperature for 2.5hours. The suspension was filtered, and the filtrate was concentrated.The residue was chromatographed on silica gel, eluting with 3:1hexane:EtOAc, to give the title compound.

¹H NMR (CDCl₃): δ 1.40 (d, 6H), 3.62-3.69 (m, 1H), 8.97 (s, 1H), 10.17(s, 1H).

EXAMPLE A-5

5-iso-Propyl-thiazole-4-carbaldehyde

A solution of 6.8 g (37 mmol) of 5-isopropyl-thiazole-4-carboxylic acidmethyl ester (J. Chem. Soc., Perkin Trans. 1, 1982:159-164) in CH₂Cl₂(120 mL) was cooled to −78° C. under nitrogen and treated dropwise withDIBAL (37 mL of 1.0 M in CH₂Cl₂; 37 mmol). The mixture was stirred atlow temperature for 45 minutes and then treated with another 20 mL ofDIBAL. The solution was stirred for 1 hour at −78° C. H₂O was added, andthe mixture was extracted with EtOAc (3×150 mL). The combined extractswere washed with brine, dried (MgSO₄), and concentrated. Chromatographyof the residue over silica gel, eluting with 2:1 hexane:EtOAc, gave thetitle compound.

¹H NMR (CDCl₃): δ 1.34 (d, 6H), 4.09-4.16 (m, 1H), 8.63 (s, 1H), 10.20(s, 1H).

EXAMPLE A-6

4-iso-Propyl-thiazole-2-carbaldehyde

A solution of 2.1 g (11 mmol) of 4-isopropyl-thiazole-2-carboxylic acidethyl ester (J. Med. Chem., 1998:602-617) in CH₂Cl₂ (50 mL) was cooledto −78° C. under nitrogen and treated dropwise with DIBAL (12 mL of 1.0M in CH₂Cl₂; 12 mmol). The mixture was stirred at low temperature for 1hour and then treated with another 7 mL of DIBAL. The solution wasstirred for 30 minutes at −78° C. H₂O was added, and the mixture wasextracted with EtOAc (3×100 mL). The combined extracts were washed withbrine, dried (MgSO₄), and concentrated. Chromatography of the residueover silica gel, eluting with 3:1 hexane:EtOAc, gave the title compound.

¹H NMR (CDCl₃): δ 1.35 (d, 6H), 3.16-3.23 (m, 1H), 7.33 (s, 1H), 9.96(s, 1H).

The remaining aldehydes were either commercially available or known inthe chemical literature, as summarized in Table A below.

TABLE A Preparation of Aldehydes Example Aryl Method of Preparation ¹HNMR Data A-7

Commercially available A-8

Synthesis, 1987:998-1001 (CDCl₃): δ 8.22(s, 1H), 8.88(s, 1H), 10.10(s,1H). A-9

Synthesis, 1987:998-1001 (CDCl₃): δ 8.51(s, 1H), 9.10(s, 1H), 10.10(s,1H). A-10

Acta. Chemica Scandinavica, 1966:20:2649-2657 (CDCl₃): δ 2.49(s, 3H),7.29(s, 1H), 9.86(s, 1H). A-11

Acta. Chemica Scandinavica, 1966,20:2649-2657 (CDCl₃): δ 2.51(s, 3H),7.71(s, 1H), 9.80(s, 1H). A-12

J. Amer. Chem. Soc., 1982:4934-4943 (CDCl₃): δ 2.76(s, 3H), 8.94(s, 1H),10.11(s, 1H). A-13

Bull. Chim. France, 1967:2235-2238 (CDCl₃): δ 2.19(s, 3H), 7.74(s, 1H),9.77(s, 1H), 11.69 (br s, 1H). A-14

Commercially available A-15

Commercially available A-16

Commercially available A-17

Commercially available A-18

J. Org. Chem., 1990;55(26):6317-6328 (CDCl₃): δ 6.69(m, 1H), 6.85(m,1H), 7.46(m, 1H), 9.2(br s, 1H), 9.82 (s, 1H). A-19

Commercially available A-20

Commercially available A-21

Commercially available A-22

Commercially available A-23

Commercially available A-24

Commercially available A-25

Commercially available A-26

Commercially available A-27

Commercially available A-28

Commercially available A-29

Commercially available A-30

Chem Pharm. Bull., 1986;34(10):4116-4125 (CDCl₃): δ 6.67(m, 1 H),7.25(m, 1H), 7.45(d, 1H), 7.74(d, 1H), 8.15(s, 1H), 8.70(br s, 1H),10.00 (s, 1H). A-31

J.O.C., 1987;53:107-109 A-32

Commercially available A-33

Commercially available A-34

Commercially available A-35

Commercially availableMethods for the Preparation of Enones: General Method 1. Preparation ofEnones via Triphenylarsonium Salts

A mixture of the appropriate aldehyde from Examples A-1 to A-29 (1.0equiv.), the crude arsonate salt (usually(3-methyl-2-oxobutyl)triphenylarsonium bromide, prepared in Synthesis,1988:975-977; 1.1 equiv.), potassium carbonate (1.1 equiv.), and 1% H₂Oin CH₃CN was stirred for 1 to 18 hours at room temperature. The solidswere filtered, and the filtrate was chromatographed on silica gel toremove the arsenate by-products.

EXAMPLE B-1

4-Methyl-1-(4-methyl-thiazol-5-yl)-pent-1-en-3-one

The title compound was prepared as described in General Method 1 using1.4 g (11.0 mmol) of 4-methyl-5-thiazolecarbaldehyde (Example A-12), 6.2g (13.1 mmol) of (3-methyl-2-oxobutyl)triphenylarsonium bromide, 1.8 g(13.1 mmol) of potassium carbonate, 75 mL of acetonitrile, and 0.75 mLof H₂O. Chromatography of the residue, eluting with 3:1 hexane:EtOAcgave the title compound.

¹H NMR (CDCl₃): δ 1.13 (d, 6H), 2.54 (s, 3H), 2.75-2.82 (m 1H), 6.50 (d,1H), 7.73 (d, 1H), 8.66 (s, 1H).

General Method 2. Preparation of Enones via Condensation with Ba(OH)₂

The desired enones were prepared by reaction of the appropriatemethylketones and aldehydes by the methods described in Synthesis,1983:502-504; An. Quim, Ser. C, 198 1;77(2):222-224; Org. Synth. Coll.,1941; 1:78; and Pol. J. Chem., 1982;56(10-112): 1435. To a reactionflask was added aldehyde (1-2 equiv.), ketone (1-2 equiv.), 95% EtOH,and anhydrous or hydrated Ba(OH)₂ (23 mg/mmol). The reaction was stirredat room temperature or heated at reflux for up to 2 days. The reactionwas cooled to room temperature. The EtOH was evaporated, and the crudereaction was partitioned between EtOAc and 1N HCl. The aqueous layer wasextracted with EtOAc. The combined organic extracts were dried (MgSO₄)and concentrated. The crude product was purified by flash chromatographyor recrystallization.

EXAMPLE B-2

1-Furan-2-yl-4-methyl-pent-1-en-3-one

The titled compound was prepared according to General Method 2 byreacting 2-furaldehyde (117 mmol), 2-methyl-butan-3-one (117 mmol),anhydrous Ba(OH)₂ (2.2 g) and EtOH (200 mL) to afford the desirecompound.

¹H NMR (CDCl₃): δ 1.18 (d, 6H), 2.83 (m, 1H), 6.46 (m, 1H), 6.65 (m,1H), 6.73 (d, 1H), 7.38 (d, 1H), 7.50 (m, 1H).

The following enones were prepared using either General Method 1 (thearsonate salt) or General Method 2 (the Ba(OH)₂ method) from thecorresponding aldehydes in Examples A-1 to A-35:

TABLE B Preparation of Enones

NMR Data (δ for vinyl protons. Solvent: CDCl₃) Example R₇ General Methodof Mass Spec B-3

Gen. Method 1 7.05, 7.64 B-4

Gen. Method 1 7.14, 7.53 B-5

Gen. Method 1 6.58, 7.72 B-6

Gen. Method 1 6.90, 7.52 B-7

Gen. Method 1 7.01, 7.57 B-8

Gen. Method 1 7.06, 7.43 B-9

Gen. Method 1 7.12, 7.54 B-10

Gen. Method 1 7.11, 7.49 B-11

Gen. Method 1 6.52, 7.78 B-12

Gen. Method 1 7.24, 7.64 B-13

Gen. Method 1 6.95, 7.60 B-14

Gen. Method 1 6.93, 7.41 B-15

Gen. Method 1 7.33, 7.60 B-16

Gen. Method 1 6.96, 7.51 B-17

Gen. Method 1 MS (APCI): 243 (M + H) B-18

Gen. Method 1 MS (APCI): 243 (M + H) B-19

Gen. Method 1 MS (APCI): 243 (M + H) B-20

Gen. Method 1 MS (APCI): 261 (M + H) B-21

Gen. Method 1 MS (APCI): 261 (M + H) B-22

Gen. Method 1 MS (APCI): 200 (M + H) B-23

Gen. Method 2 6.74, 7.86 B-24

Gen. Method 2 6.90, 7.73 B-25

Gen. Method 2 6.74, 7.57 B-26

Gen. Method 2 6.80, 7.56 B-27

Gen. Method 2 B-28

Gen. Method 1 MS (APCI): 164 (M + H) B-29

Gen. Method 1 MS (APCI): 165 (M + H) B-30

Gen. Method 2 6.59, 7.56 B-31

Gen. Method 1 6.82, 7.78 B-32

Gen. Method 1 6.78, 6.99 B-33

Gen. Method 2 7.11, 7.70 B-34

Gen. Method 2 6.79, 7.49 B-35

Gen. Method 2 6.84, 7.66 B-36

Gen. Method 2 6.73, 7.43

Names corresponding to the enones in Table B above are:

-   -   B-3: 4-Methyl-1-thiazol-2-yl-pent-1-en-3-one;    -   B-4: 4-Methyl-1-thiazol-4-yl-pent-1-en-3-one;    -   B-5: 4-Methyl-1-thiazol-5-yl-pent-1-en-3-one;    -   B-6: 4-Methyl-1-(5-methyl-thiazol-2-yl)-pent-1-en-3-one;    -   B-7: 4-Methyl-1-(4-methyl-thiazol-2-yl)-pent-1-en-3-one;    -   B-8: 4-Methyl-1-(2-methyl-thiazol-4-yl)-pent-1-en-3-one;    -   B-9: 4-Methyl-1-(5-methyl-thiazol-4-yl)-pent-1-en-3-one;    -   B-10: 1-(2-Isopropyl-thiazol-4-yl)-4-methyl-pent-1-en-3-one;    -   B-11: 1-(4-Isopropyl-thiazol-5-yl)-4-methyl-pent-1-en-3-one;    -   B-12: 1-(5-Isopropyl-thiazol-4-yl)-4-methyl-pent-1-en-3-one;    -   B-13: 1-(4-Isopropyl-thiazol-2-yl)-4-methyl-pent-1-en-3-one;    -   B-14: N-[4-(4-Methyl-3-oxo-pent-1-enyl)-thiazol-2-yl]-acetamide;    -   B-15: 4-Methyl-1-pyridin-2-yl-pent-1-en-3-one;    -   B-16: 4-Methyl-1-pyridin-4-yl-pent-1-en-3-one;    -   B-17: 4-Methyl-1-(2-trifluoromethyl-phenyl)-pent-1-en-3-one;    -   B-18: 4-Methyl-1-(3-trifluoromethyl-phenyl)-pent-1-en-3-one;    -   B-19: 4-Methyl-1-(4-trifluoromethyl-phenyl)-pent-1-en-3-one;    -   B-20:        4-Methyl-1-(3-fluoro-5-trifluoromethyl-phenyl)-pent-1-en-3-one;    -   B-21:        4-Methyl-1-(4-fluoro-3-trifluoromethyl-phenyl)-pent-1-en-3-one;    -   B-22: 4-(4-Methyl-3-oxo-pent-1-enyl)-benzonitrile;    -   B-23: 4-Methyl-1-(3-fluoro-2-methyl-phenyl)-pent-1-en-3-one;    -   B-24: 4-Methyl-1-(2-fluoro-phenyl)-pent-1-en-3-one;    -   B-25: 4-Methyl-1-(4-fluoro-phenyl)-pent-1-en-3-one;    -   B-26: 4-Methyl-1-(3-fluoro-phenyl)-pent-1-en-3-one;    -   B-27: 4-Methyl-1-(3,4-difluoro-phenyl)-pent-1-en-3-one;    -   B-28: 4-Methyl-1-(1H-pyrrol-3-yl)-pent-1-en-3-one;    -   B-29: 1-(1H-Imidazol-4-yl)-4-methyl-pent-1-en-3-one;    -   B-30: 4-Methyl-1-thiophen-3-yl-pent-1-en-3-one;    -   B-31: 1-(1H-Indol-5-yl)-4-methyl-pent-1-en-3-one;    -   B-32: 4-Methyl-1-(2-methyl-thiophen-3-yl)-pent-1-en-3-one;    -   B-33: 4-Methyl-1-(2,6-difluoro-phenyl)-pent-1-en-3-one;    -   B-34: 4-Methyl-1-(3,5-difluoro-phenyl)-pent-1-en-3-one;    -   B-35: 4-Methyl-1-(2,4-difluoro-phenyl)-pent-1-en-3-one; and    -   B-36: 4-Methyl-1-(3,4,5-trifluoro-phenyl)-pent-1-en-3-one.        Methods for the Preparation of Requisite Ketones: General        Method 3. Preparation of Ketones by Hydrogenation of Enones

The substituted arylpropiophenones were prepared by hydrogenation of thecorresponding enones at room temperature at 50 psi in tetrahydrofuran(THF) utilizing a number of catalysts such as: 5% palladium (Pd) onbarium sulfate (BaSO₄) or (Ph₃P)₃RhCl or 10% Pd on carbon or 5% Pd onCaCO₃. The catalyst was filtered off and the resulting ketonerecrystallized or purified by flash chromatography.

EXAMPLE C-1

4-Methyl-1-pyridin-4-yl-pentan-3-one

The title compound was prepared according to General Method 3 using4-methyl-1-pyridin-4-yl-pent-1-en-3-one (Example B-16; 1.81 g),(Ph₃P)₃RhCl (0.5 g), and THF (100 mL) at 50 psi. The title compound wasflash chromatographed using 98:2 CH₂Cl₂:MeOH as eluent. ¹H NMR (CDCl₃):δ 1.15 (d, 6H), 2.5-2.7 (m, 1H), 2.7-2.8 (m, 2H), 2.85-2.95 (m, 2H), 7.1(d, 2H), 8.5 (d, 2H).

EXAMPLE C-2

4-Methyl-1-(4-methyl-thiazol-5-yl)-pentan-3-one

The title compound was prepared as described in General Method 3 using1.73 g (8.86 mmol) of 4-methyl-1-(4-methyl-thiazol-5-yl)-pent-1-en-3-one(prepared in Example B-1) and 0.4 g of 5% Pd/BaSO₄ in THF:MeOH (25 mL:25mL). The crude product was chromatographed on silica gel, eluting with2:1 hexane:EtOAc, to give the title compound. ¹H NMR (CDCl₃): δ 1.03 (d,6H), 2.35 (s, 3H), 2.49-2.56 (m, 1H), 2.72 (t, 2H), 2.98 (t, 2H), 8.49(s, 1H).

Synthesis of Appropriate Halogenated Heterocycles Necessary for KetoneSynthesis (General Methods 4a and 4b)

EXAMPLE STARTING MATERIAL-1 (SM)

(5-Bromo-thiophen-2-yl)-methanol

The title compound was prepared by reduction of5-bromo-2-thiophenecarbaldehyde (137 mmol) with sodium borohydride (137mmol) in MeOH (500 mL). The reaction was stirred for 2 hours at 0° C.and 2 hours at room temperature. The MeOH was evaporated, and saturatedammonium chloride was added followed by 2N HCl. The aqueous layers wereextracted with EtOAc, dried (MgSO₄), and concentrated. Flashchromatography over silica gel using 100% CH₂Cl₂ as eluent afforded thetitle compound. ¹H NMR (CDCl₃): δ 4.74 (d, 2H), 6.75 (m, 1H), 6.91 (d,1H).

EXAMPLE STARTING MATERIAL-2

(4-Bromo-thiophen-2-yl)-methanol

The title compound was prepared in a similar manner to Example SM-1 byreduction of 4-bromo-2-thiophenecarboxaldehyde (122 mmol) with sodiumborohydride (12 mmol) in MeOH (500 mL).

¹H NMR (CDCl₃): δ 4.80 (d, 2H), 6.93 (d, 1H), 7.18 (d, 1H).

EXAMPLE STARTING MATERIAL-3

(3-Bromo-thiophen-2-yl)-methanol

The title compound was prepared by reduction of3-bromothiophene-2-carboxylic acid methyl ester (45 mmol) with lithiumaluminum hydride (45 mmol) in THF (150 mL) at 0° C. for 1 hour and thenovernight at room temperature. The reaction was worked up by addition of1 mL of H₂O, 1 mL of 15% NaOH, and 3 mL of H₂O followed by filtrationthrough celite. Concentration of the filtrate gave the title compound. ¹H NMR (CDCl₃): δ 4.80 (s, 2H), 6.96 (d, 1H), 7.26 (d, 1H).

EXAMPLE STARTING MATERIAL-4

1-Trityl-4-iodopyrazole

The title compound was prepared by combining 4-iodopyrazole (10 g, 52mmol), triphenylmethyl chloride (14.4 g, 51.6 mmol), triethylamine(NEt₃) (7.2 mL, 52 mmol), and DMF (80 mL). After stirring overnight, themixture was poured onto ice water. The precipitated solid was collectedand recrystallized to give the title compound as a solid, mp 193-194° C.

¹H NMR (CDCl₃): δ 7.11 (m, 6H), 7.32 (m, 9H), 7.41 (s, 1H), 7.67 (s,1H).

EXAMPLE STARTING MATERIAL-5 (SM)

(4-Bromo-thiophen-3-yl)-methanol

The title compound was prepared in a similar manner to Example SM-1 byreduction of 4-bromo-3-thiophenecarbaldehyde (Bull. Soc. Chim. France,1967;11:4115) with sodium borohydride in MeOH. ¹H NMR (CDCl₃): δ 2.05(s, 2H), 7.27-7.34 (m, 2H).

EXAMPLE STARTING MATERIAL-6 (SM)

(2-Bromo-thiophen-3-yl)-methanol

A solution of 10.0 g (39.0 mmol) of 2-bromo-3-bromomethyl-thiophene (J.Chem. Soc. Perkin Trans. II, 1983:813) in 130 mL of acetone was treatedwith a solution of 11.4 g (67.1 mmol) of AgNO₃ in 110 mL of H₂O. Themixture was stirred at room temperature for 1 hour and filtered. Thesolid was washed with Et₂O and acetone; the combined filtrate andwashings were concentrated. The residue was extracted with CH₂Cl₂, andthe organic layer was dried (MgSO₄) and concentrated. The crude productwas chromatographed over silica gel, eluting with hexane:EtOAc:CH₂Cl₂(80:5:15 to 60:30:10) to give the title compound.

¹H NMR (CDCl₃) δ 1.67 (t, 1H), 4.63 (d, 2H), 7.03 (d, 1H), 7.26 (d, 1H).

EXAMPLE STARTING MATERIAL-7 (SM)

3-Bromo-4-ethyl-fluorobenzene

2-Bromo-4-fluoroacetophenone (10.0 g, 46.1 mmol) in THF (120 mL) wastreated with BF₃.OEt₂ (22.9 g, 20.4 mL, 161 mmol) and followed byNaBH₃CN (7.24 g, 155 mmol) added portionwise. The resulting mixture washeated to reflux under N₂ overnight and then cooled to room temperature.Diethyl ether (Et₂O) was added; the organic layer was washed withsaturated NaHCO₃/H₂O and brine, dried (MgSO₄), filtered, andconcentrated. The resulting residue was subjected to flash silica gelchromatography, eluting with 4:1 (hexanes:EtOAc) to afford theintermediate alcohol. ¹H NMR (CDCl₃): δ 1.46 (d, 3H), 1.98 (bs, 1H),5.21 (q, 1H), 7.03-7.10 (m, 1H), 7.26 (dd, 1H), 7.58 (dd, 1H).

The alcohol isolated above (4.0 g, 18 mmol) was dissolved in hexanes (20mL) and treated with trimethylsilyl chloride (11.9 g, 13.9 mL, 109mmol), NaI (16.4 g, 109 mmol), and CH₃CN (5.7 mL, 109 mmol). Theresulting slurry was stirred at room temperature under N₂ overnight.Et₂O was added followed by H₂O. The phases were separated, and theaqueous phase was extracted again with Et₂O; the combined organic phaseswere washed with sodium bisulfite (NaHSO₃)/H₂O and brine, dried (MgSO₄),filtered, and concentrated. The resulting residue was subjected to flashsilica gel chromatography, eluting with hexanes to afford the titlecompound. ¹H NMR (CDCl₃): δ 1.20 (t, 3H), 2.72 (q, 2H), 6.93-6.99 (m,1H), 7.18 (dd, 1H), 7.27 (dd, 1H).

EXAMPLE STARTING MATERIAL-8 (SM)

(2-Bromo-5-fluoro-phenyl)-methanol

2-Bromo-5-fluorobenzylbromide (2.0 g, 7.46 mmol) was dissolved indioxane (25 mL) and H₂O (25 mL), and CaCO₃ (3.84 g, 38.39 mmol) wasadded. The mixture was heated to reflux overnight. The solution wasconcentrated, and the residue was partitioned between H₂O and CH₂Cl₂.The organic phase was washed with 1N HCl and brine, dried (MgSO₄),filtered, and concentrated to afford the title compound. ¹H NMR (CDCl₃):δ 2.00 (t, 1H), 4.72 (d, 2H), 6.85-6.92 (m, 1H), 7.26 (dd, 1H), 7.48(dd, 1H).

The remaining halides were commercially available, as summarized inTable C below.

TABLE C Aryl Halides Example Aryl SM-9

SM-10

SM-11

SM-12

SM-13

SM-14

SM-15

SM-16

SM-17

SM-18

SM-19

Methods for the Preparation of Requisite Ketones: General Method 4a and4b. Preparation of Ketones via Pd-Catalyzed Coupling

General Method 4a is the method described in Tetrahedron, 1979;35:329and Tetrahedron Letters, 1991;32:2121. The appropriate aryl halide (Bror I; 1 equiv.), allylic alcohol (1-2 equiv.), tetrabutyl ammoniumchloride (1 equiv.), sodium bicarbonate (2-3 equiv.), DMF (0.1-1 mL permmol of halide), and palladium acetate (0.01-0.1 equiv.) were added to areaction vessel. The solution was heated to 40° C. to 100° C. for 1 to24 hours. On occasion, pyrrolidine (0.2-1 equiv.) was also added. Thereaction was cooled to room temperature and partitioned between H₂O andCH₂Cl₂. The solution was filtered through celite and the aqueous layerextracted two times with CH₂Cl₂. The organic extracts were washed withbrine and then dried (MgSO₄). Purification was usually carried out byflash chromatography.

General Method 4b is the method described in Tetrahedron,1979;35:329-340 with slight modifications. The appropriate aryl halide(Br or I; 1 equiv.), allylic alcohol (1-2 equiv.), sodium iodide(0.01-0.050 equiv.), sodium bicarbonate (1-3 equiv.), triphenylphosphine (0.01-0.050 equiv.), DMF (0.1-1 mL per mmol of halide), andpalladium acetate (0.01-0.1 equiv.) were added to a reaction vessel. Thesolution was heated to 40° C. to 100° C. for 1 to 24 hours. Pyrrolidine(0.2-1 equiv.) was also added at times. The reaction was cooled to roomtemperature and partitioned between H₂O and CH₉Cl₂. The solution wasfiltered through celite and the aqueous layer extracted two times withCH₂Cl₂. The organic extracts were washed with brine and then dried(MgSO₄). Purification was usually carried out by flash chromatography.

EXAMPLE C-3

4-Methyl-1-pyridin-3-yl-pentan-3-one

The title compound was prepared according to General Method 4a using3-iodo-pyridine (36.6 mmol), 4-methyl-1-penten-3-ol (54.9 mmol),tetrabutyl ammonium chloride (36.6 mmol), sodium bicarbonate (91.5mmol), pyrrolidine (˜1.5 mL), DMF (15 mL), and palladium acetate (0.51g). The title compound was flash chromatographed eluting withEtOAc:CH₂Cl₂:hexane 50:25:25.

¹NMR (CDCl₃): δ 1.15 (d, 6H), 2.5-2.7 (m, 1H), 2.7-2.9 (m, 2H),2.85-2.95 (m, 2H), 7.2-7.3 (m, 1H), 7.5-7.6 (m, 1H), 8.4-8.5 (m, 2H).

EXAMPLE C-4

1-Furan-3-yl-4-methyl-pentan-3-one

The title compound was prepared according to General Method 4a using3-bromofuran (17 mmol), 4-methyl-1-penten-3-ol (25.5 mmol), tetrabutylammonium chloride (17 mmol), sodium bicarbonate (42.5 mmol), DMF (15mL), and palladium acetate (0.9 mmol). The title compound was flashchromatographed eluting with EtOAc:hexane (5:95 to 10:90).

¹NMR (CDCl₃): δ 1.05 (d, 6H), 2.5-2.7 (m, 1H), 2.65 (s, 4H), 6.2 (s,1H), 7.25 (m, 1H), 7.3 (m, 1H).

EXAMPLE C-5

4-Methyl-1-thiophen-3-yl-pentan-3-one

The title compound was prepared according to General Method 4b using3-bromothiophene (20 mmol), 4-methyl-1-penten-3-ol (30 mmol), sodiumiodide (0.7 mmol), sodium bicarbonate (24 mmol), triphenylphosphine (0.6mmol), DMF (15 mL), and palladium acetate (0.2 mmol). The title compoundwas flash chromatographed using EtOAc:hexane (5:95 to 10:90).

¹NMR (CDCl₃): δ 1.05 (d, 6H), 2.5-2.7 (m, 1H), 2.7-2.8 (t, 2H),2.85-2.95 (t, 2H), 6.90-9.95 (m, 2H), 7.2-7.3 (m, 1H).

Alternatively, the title compound could be prepared by hydrogenation(General Method 3) of the enone prepared in Example B-30.

General Method 5. Preparation of Silylated Intermediates.

The appropriate alcohol (1 equiv.), and imidazole (1.2 equiv.) wereadded to a reaction vessel followed by CH₂Cl₂ or THF (7-10 mL per mmolof alcohol), t-Butyldimethylsilyl chloride (1.1 equiv.) was added andthe reaction stirred at room temperature (3 hours to 4 days). Thereaction was filtered, washed with H₂O and brine, dried (MgSO₄), andconcentrated. The product was either flashed chromatographed or carriedon crude.

EXAMPLE C-6

1-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-4-methyl-pentan-3-one

The title compound was prepared according to General Method 5 using1-(5-hydroxymethyl-thiophen-2-yl)-4-methyl-pentan-3-one (see ExampleC-24 below; 73.0 mmol), t-butyldimethylsilyl chloride (80.3 mmol),imidazole (80.3 mmol) and CH₂Cl₂ (300 mL). ¹H NMR (CDCl₃): δ 0.09 (s,6H), 0.92 (s, 9H), 1.09 (d, 6H), 2.59 (m, 1H), 2.81 (t, 2H), 3.06 (t,2H), 4.78 (s, 2H), 6.61 (d, 1H), 6.69 (d, 1H).

The following ketones were prepared as indicated [either from reductionof the corresponding enones from Examples B-1 to B-36 (General Method 3)OR from the corresponding halides from Examples SM-1 to SM-19 (GeneralMethod 4a or 4b)]. In some cases, the following ketones were alsoprepared from silylation of an existing ketone using General Method 5:

TABLE D Preparation of Ketones

General Analytical Data Example R₈ Method (¹H NMR or MS) C-7 

Gen. Method 3 (CDCl₃): δ 1.06(d, 6H), 2.56-2.63(m, 1H), 2.97(t, 2H),3.24(t, 2H), 7.13(d, 1H), 7.60(d, 1H) C-8 

Gen. Method 3 (CDCl₃): δ 1.04(d, 6H), 2.53-2.60(m, 1H), 2.87(m, 2H),3.08(m, 2H), 6.96(m, 1H), 8.70(m, 1H) C-9 

Gen. Method 3 (CDCl₃): δ 1.08(d, 6H), 2.55-2.61(m, 1H), 2.78(t, 2H),3.15(t, 2H), 7.60(s, 1H), 8.63(s, 1H) C-10

Gen. Method 3 (CDCl₃): δ 1.03(d, 6H), 2.33(s, 3H), 2.52-2.59(m, 1H),2.88-2.92(m, 2H), 3.09-3.13(m, 2H), 7.18(s, 1H) C-11

Gen. Method 3 (CDCl₃): δ 1.05(d, 6H), 2.34(s, 3H), 2.55-2.62(m, 1H),2.93(t, 2H), 3.18(t, 2H), 6.65(s, 1H) C-12

Gen. Method 3 (CDCl₃): δ 1.02(d, 6H), 2.50-2.56(m, 1H), 2.62(s, 3H),2.80-2.84(m, 2H), 2.91-2.94(m, 2H), 6.68(s, 1H) C-13

Gen. Method 3 (CDCl₃): δ 1.00(d, 6H), 2.35(s, 3H), 2.50-2.57(m, 1H),2.86(s, 4H), 8.45(s, 1H) C-14

Gen. Method 3 (CDCl₃): δ 1.02(d, 6H), 1.32(d, 6H), 2.52-2.58(m, 1H),2.83(t, 2H), 2.95(t, 2H), 3.20-3.27(m, 1H), 6.70(s, 1H) C-15

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 1.26(d, 6H), 2.53-2.60(m, 1H),2.75(t, 2H), 3.04(t, 2H), 3.07-3.14(m, 1H), 8.56(s, 1H) C-16

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 1.27(d, 6H), 2.56-2.63(m, 1H),2.89-2.97(m, 4H), 3.28-3.35(m, 1H), 8.53(s, 1H) C-17

Gen. Method 3 (CDCl₃): δ 1.10(d, 6H), 1.26(d, 6H), 2.60-2.65(m, 1H),2.98(t, 2H), 2.99-3.05(m, 1H), 3.24(t, 2H), 6.68(s, 1H) C-18

Gen. Method 3 (CDCl₃): δ 1.04(d, 6H), 2.20(s, 3H), 2.52-2.59(m, 1H),2.76-2.80(m, 2H), 2.86-2.90(m, 2H), 6.51(s, 1H) C-19

Gen. Method 3 (CDCl₃): δ 1.15(d, 6H), 2.5-2.7(m, 1H), 2.9-3.0(m, 2H),3.0-3.1(m, 2H), 7.05- 7.15(m, 1H), 7.2(d, 1H), 7.5- 7.6(dt, 1H), 8.5(d,1H) C-20

Gen. Method 3 (CDCl₃): δ 1.15(d, 6H), 2.5-2.7(m, 1H), 2.7-2.9(m, 2H),2.85-2.95(m, 2H), 5.95(m, 1H), 6.25(m, 1H), 7.3(m, 1H) C-21

Gen. Method 3 (complete reduction of C-20) MS(APCI): 171(M + H) C-22

Gen. Method 4b (CDCl₃): δ 1.1(d, 6H), 2.5-2.7(m, 1H), 2.8-2.9(t, 2H),3.05-3.15(t, 2H), 6.75- 6.80(m, 1H), 6.85-6.95(m, 1H), 7.05-7.15(m, 1H)C-23

Gen. Method 4b (CDCl₃): δ 1.1(d, 6H), 2.5-2.7(m, 1H), 2.7-2.8(m, 2H),2.8-2.9(m, 2H), 4.75(s, 2H), 6.85(s, 1H), 6.9(s, 1H) C-24

Gen. Method 4b (CDCl₃): δ 1.1(d, 6H), 2.5-2.7(m, 1H), 2.8-2.9(t, 2H),3.05-3.15(t, 2H) 4.75(s, 2H), 6.65(d, 1H), 6.8(d, 1H) C-25

Gen. Method 4b (CDCl₃): δ 1.0(d, 6H), 2.4-2.5(m, 1H), 2.7-2.8(m, 2H),2.8-2.9(m, 2H), 4.7(s, 2H), 6.75(d, 1H), 7.1(d, 1H) C-26

Gen. Method 5 (from C-25) (CDCl₃): δ 0.00(s, 6H), 0.82(s, 9H), 0.95(d,6H), 2.44(m, 1H), 2.62(t, 2H), 2.72(t, 2H), 4.70(s, 2H), 6.70(d, 1H),7.01(d, 1H) C-27

Gen. Method 5 (from C-23) (CDCl₃): δ 0.09(s, 6H), 0.85(s, 9H), 0.92(d,6H), 2.58(m, 1H), 2.73(m, 2H), 2.82(m, 2H), 4.81(s, 2H), 6.74(s, 1H),6.82(s, 1H) C-28

Gen. Method 3 (CDCl₃): δ 1.08(d, 6H), 2.21(d, 3H), 2.53-2.62(m, 1H),2.70(t, 2H), 2.89(t, 2H), 6.84- 6.92(m, 2H), 7.03-7.10(m, 1H) C-29

Gen. Method 3 C-30

Gen. Method 3 (CDCl₃): δ 1.05(d, 6H), 2.50-2.60(m, 1H), 2.71- 2.76(m,2H), 2.83-2.89(m, 2H), 6.95(m, 2H), 7.13(m, 2H) C-31

Gen. Method 4a ¹HNMR(CDCl₃): δ 1.04(d, 6H), 2.55(sp, 1H), 2.64-2.74(m,4H), 7.11-7.17(m, 7H), 7.26- 7.35(m, 9H), 7.48(s, 1H) C-32

Gen. Method 3 MS(APCI): 166(M + H) C-33

Gen. Method 3 MS(APCI): 167(M + H) C-34

Gen. Method 4a MS(APCI): 179(M + H) C-35

Gen. Method 4a MS(APCI): 194(M + H) C-36

Gen. Method 3 MS(APCI): 200(M − H) C-37 Ph Prepared as reported in Bull.Soc. Chim. Fr., 1956: 1653. C-38

Gen. Method 4 MS(APCI): 206(M) C-39

Gen. Method 5 (from C-38) MS(APCI): 319(M − H) C-40

Gen. Method 3 ¹HNMR(CDCl₃): δ 1.09(d, 6H), 2.56-2.63(m, 1H), 2.84(t,2H), 3.01(t, 2H), 6.49(m, 1H), 7.03-7.06(m, 1H), 7.17(m, 1H),7.29-7.33(m, 1H), 7.46(s, 1H), 8.23(s, 1H) C-41

Gen. Method 4b (CDCl₃): δ 1.03(d, 6H), 2.51-2.58(m, 1H), 2.81- 2.87(m,4H), 4.60(s, 2H), 6.90(d, 1H), 7.17(d, 1H) C-42

Gen. Method 5 (from ABOVE) (CDCl₃): δ 0.0(s, 6H), 0.83(s, 9H), 0.99(d,6H), 2.50(m, 1H), 2.71(m, 4H), 4.56(s, 2H), 6.81(d, 1H), 7.06(s, 1H)C-43

Gen. Method 4b (CDCl₃): δ 1.09(d, 6H), 2.19(s, 3H), 2.60(m, 1H), 2.75-2.80(m, 4H), 6.85-6.90(m, 2H) C-44

Gen. Method 4b (CDCl₃): δ 1.04-1.06(d, 6H), 2.13(s, 3H), 2.51-2.58(m,1H), 2.72-2.75(t, 2H), 2.94-2.98(t, 2H), 6.72-6.75(d, 1H), 6.97-6.98(d,1H) C-45

Gen. Method 3 (CDCl₃): δ 1.06(d, 6H), 2.37(s, 3H), 2.52-2.59(m, 1H),2.67-2.71(t, 2H), 2.77-2.81(t, 2H), 6.78-6.79(d, 1H), 6.98-7.00(d, 1H)C-46

Gen. Method 4a (CDCl₃): δ 1.05(d, 6H), 2.50-2.61(m, 1H), 2.88(t, 2H),3.12(t, 2H), 4.62(d, 2H), 6.96(d, 1H), 7.08(d, 1H) C-47

Gen. Method 5 (from C-46) (CDCl₃): δ 0.08(s, 6H), 0.91(s, 9H), 1.08(d,6H), 2.50-2.70(m, 1H), 2.78-2.81(t, 2H), 3.03-3.08(t, 2H), 4.63(s, 2H),6.94(d, 1H), 7.03(d, 1H) C-48

Gen. Method 3 (CDCl₃): δ 1.09(d, 6H), 2.52-2.66(m, 1H), 2.71-2.76(m,2H), 2.90-2.95(m, 2H), 6.79- 6.89(m, 2H), 7.09-7.19(m, 1H) C-49

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 2.50-2.64(m, 1H), 2.73-2.78(m,2H), 2.84-2.90(m, 2H), 6.59- 6.67(m, 2H), 7.69-7.72(m, 1H) C-50

Gen. Method 3 (CDCl₃): δ 1.06(d, 6H), 2.51-2.60(m, 1H), 2.71-2.77(m,2H), 2.84-2.89(m, 2H), 6.72- 6.81(m, 2H), 7.12-7.20(m, 1H) C-51

Gen. Method 3 (CDCl₃): δ 1.07(d, 6H), 2.49-2.61(m, 1H), 2.71-2.76(m,2H), 2.80-2.85(m, 2H), 6.74-6.84(m, 2H) C-52

Gen. Method 4a C-53

Gen. Method 4a (CDCl₃): δ 1.10(d, 6H), 1.19(t, 3H), 2.54-2.64(m, 3H),2.69-2.77(m, 2H), 2.82-2.90(m, 2H), 6.80-6.87(m, 2H), 7.08-7.13(m, 1H)C-54

Gen. Method 4a (CDCl₃): δ 1.04(d, 6H), 2.37(bs, 1H), 2.50-2.66(m, 1H),2.77-2.82(m, 2H), 2.84-2.94(m, 2H), 4.70(s, 2H), 6.88-6.91(m, 1H),7.08-13(m, 2H) C-55

Gen. Method 5 (from C-54) C-56

Gen. Method 4a

EXAMPLE C-57

2,2,2-Trifluoro-N-[4-(4-methyl-3-oxo-pentyl)-thiazol-2-yl]-acetamide

A solution of C-18 (from Table D above; 1.21 g, 5.03 mmol) in 6N HCl (50mL) and THF (5 mL) was refluxed for 4 hours and then cooled to roomtemperature. Solid NaHCO₃ was added portionwise with caution until pH7.2 was achieved. The suspension was extracted with EtOAc. The combinedextracts were washed with brine, dried (MgSO₄), and concentrated. Theresidue was chromatographed over silica gel, eluting with EtOAc, to givethe deprotected compound. ¹H NMR (CDCl₃): δ 1.04 (d, 6H), 2.52-2.59 (m,1H), 2.75 (m, 4H), 6.06 (s, 1H).

A solution of the ketone prepared above (0.75 g, 3.8 mmol) in CH₂Cl₂ (50mL) was cooled in an ice bath, treated with NEt₃ (0.6 mL, 4.3 mmol) andtrifluoromethyl acetic anhydride (0.6 mL, 4.3 mmol), and allowed to warmto room temperature. H₂O was added. The organic layer was separated,washed with brine, and dried (MgSO₄). Concentration gave an oil whichwas chromatographed over silica gel, eluting with EtOAc, to give thetitle compound. ¹ H NMR (CDCl₃): δ 1.10 (d, 6H), 2.58-2.65 (m, 1H),2.83-2.86 (m, 2H), 2.91-2.95 (m, 2H), 6.61 (s, 1H).

Names corresponding to the ketones from Table D above are:

-   -   C-7: 4-Methyl-1-thiazol-2-yl-pentan-3-one;    -   C-8: 4-Methyl-1-thiazol-4-yl-pentan-3-one;    -   C-9: 4-Methyl-1-thiazol-5-yl-pentan-3-one;    -   C-10: 4-Methyl-1-(5-methyl-thiazol-2-yl)-pentan-3-one;    -   C-11: 4-Methyl-1-(4-methyl-thiazol-2-yl)-pentan-3-one;    -   C-12: 4-Methyl-1-(2-methyl-thiazol-4-yl)-pentan-3-one;    -   C-13: 4-Methyl-1-(5-methyl-thiazol-4-yl)-pentan-3-one;    -   C-14: 1-(2-Isopropyl-thiazol-4-yl)-4-methyl-pentan-3-one;    -   C-15: 1-(4-Isopropyl-thiazol-5-yl)-4-methyl-pentan-3-one;    -   C-16: 1-(5-Isopropyl-thiazol-4-yl)-4-methyl-pentan-3-one;    -   C-17: 1-(4-Isopropyl-thiazol-2-yl)-4-methyl-pentan-3-one;    -   C-18: N-[4-(4-Methyl-3-oxo-pentyl)-thiazol-2-yl]-acetamide;    -   C-19: 4-Methyl-1-pyridin-2-yl-pentan-3-one;    -   C-20: 1-Furan-2-yl-4-methyl-pentan-3-one;    -   C-21: 4-Methyl-1-(tetrahydro-furan-2-yl)-pentan-3-one;    -   C-22: 4-Methyl-1-thiophen-2-yl-pentan-3-one;    -   C-23: 1-(5-Hydroxymethyl-thiophen-3-yl)-4-methyl-pentan-3-one;    -   C-24: 1-(5-Hydroxymethyl-thiophen-2-yl)-4-methyl-pentan-3-one;    -   C-25: 1-(2-Hydroxymethyl-thiophen-3-yl)-4-methyl-pentan-3-one;    -   C-26:        1-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-4-methyl-pentan-3-one;    -   C-27:        1-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-4-methyl-pentan-3-one;    -   C-28: 1-(3-Fluoro-2-methyl-phenyl)-4-methyl-pentan-3-one;    -   C-29: 1-(2-Fluoro-phenyl)-4-methyl-pentan-3-one;    -   C-30: 1-(4-Fluoro-phenyl)-4-methyl-pentan-3-one;    -   C-31: 4-Methyl-1-(1-trityl-1H-pyrazol-3-yl)-pentan-3-one;    -   C-32: 4-Methyl-1-(1H-pyrrol-3-yl)-pentan-3-one;    -   C-33: 1-(1H-Imidazol-4-yl)-4-methyl-pentan-3-one;    -   C-34: 4-Methyl-1-(pyrimidin-5-yl)-pentan-3-one;    -   C-35: 1-(2-Amino-pyrimidin-5-yl)-4-methyl-pentan-3-one;    -   C-36: 4-(4-Methyl-3-oxo-pentyl)-benzonitrile;    -   C-37: 4-Methyl-1-phenyl-pentan-3-one;    -   C-38: 1-(2-Hydroxymethyl-phenyl)-4-methyl-pentan-3-one;    -   C-39:        1-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-4-methyl-pentan-3-one.    -   C-40: 1-(1H-Indol-5-yl)-4-methyl-pentan-3-one;    -   C-41: 1-(4-Hydroxymethyl-thiophen-3-yl)-4-methyl-pentan-3-one;    -   C-42:        1-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-4-methyl-pentan-3-one;    -   C-43: 4-Methyl-1-(4-methyl-thiophen-3-yl)-pentan-3-one;    -   C-44: 4-Methyl-1-(3-methyl-thiophen-2-yl)-pentan-3-one;    -   C-45: 4-Methyl-1-(2-methyl-thiophen-3-yl)-pentan-3-one;    -   C-46: 1-(3-Hydroxymethyl-thiophen-2-yl)-4-methyl-pentan-3-one;    -   C-47:        1-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-4-methyl-pentan-3-one;    -   C-48: 1-(2,6-Difluoro-phenyl)-4-methyl-pentan-3-one;    -   C-49: 1-(3,5-Difluoro-phenyl)-4-methyl-pentan-3-one;    -   C-50: 1-(2,4-Difluoro-phenyl)-4-methyl-pentan-3-one;    -   C-51: 1-(3,4,5-Trifluoro-phenyl)-4-methyl-pentan-3-one;    -   C-52: 1-(5-Fluoro-2-methyl-phenyl)-4-methyl-pentan-3-one;    -   C-53: 1-(2-Ethyl-5-fluoro-phenyl)-4-methyl-pentan-3-one;    -   C-54: 1-(4-Fluoro-2-hydroxymethyl-phenyl)-4-methyl-pentan-3-one;    -   C-55:        1-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-4-methyl-pentan-3-one;        and    -   C-56: 1-(4-Fluoro-2-methyl-phenyl)-4-methyl-pentan-3-one.        General Method 6. Preparation of β-Ketoesters

Methyl acetoacetate was added dropwise to a slurry of hexane washedsodium hydride in anhydrous THF at 0° C. and the reaction stirred at 0°C. (15 minutes to 3 hours). N-Butyl lithium (nBuLi) was then added at 0°C. and the reaction stirred at 0° C. (15 minutes to 24 hours). Asolution of the requisite ketone in THF was added, and the reactionmixture was stirred at 0° C. to room temperature for 15 minutes to 24hours. To the reaction mixture was added acetic acid [or dilute HCl orsaturated ammonium chloride (NH₄Cl)] with stirring, and the THF wasremoved on a rotoevaporator. The viscous reaction mixture waspartitioned between H₂O and EtOAc. After separation of the layers, theaqueous layer was again extracted with EtOAc. The combined organicextracts were dried (MgSO₄) and concentrated. The aldol intermediateswere either purified by flash chromatography or taken on crude.

General Method 7. Desilylation of Silyl Ether Protecting Groups

The appropriate silanyloxy compound (1 equiv.) was added to a reactionvessel followed by THF (3-5 mL per mmol of silanyloxy compound). Thissolution was treated with tetrabutylammonium fluoride (1.2-2.0 equiv.)and stirred at room temperature (1 hour to 1 day). The product waspartitioned between EtOAc and 1N HCl. The organic layer was dried(MgSO₄) and concentrated. The product was either flashed chromatographedor carried on crude.

EXAMPLE D-1

5-Hydroxy-6-methyl-5-[2-(4-methyl-thiazol-5-yl)-ethyl]-3-oxo-heptanoicacid methyl ester

The title compound was prepared as described in General Method 6 from1.00 g (8.61 mmol) of methyl acetoacetate, 0.38 g (9.50 mmol) of sodiumhydride, 4.5 mL of 2.1 M nBuLi (9.45 mmol), and 1.53 g (7.75 mmol) of4-methyl-1-(4-methyl-thiazol-5-yl)-pentan-3-one (prepared in ExampleC-2.) The crude compound was used without purification in the next step.

The following compounds were prepared in similar fashion from theappropriate ketone (from Examples C-1 to C-57) and were used withoutpurification.

TABLE E Preparation of β-Ketoesters

Example R₉ D-2

D-3

D-4

D-5

D-6

D-7

D-8

D-9

D-10

D-11

D-12

D-13

D-14

D-15

D-16

D-17

D-18

D-19

D-20

D-21

D-22

D-23

D-24

D-25

D-26

D-27

D-28

D-29

D-30

D-31

D-32

D-33

D-34

D-35

D-36

D-37

D-38*

D-39

D-40

D-41

D-42

D-43

D-44

D-45

D-46

D-47

D-48

D-49

D-50

D-51

D-52**

*Can be prepared from D-37 as outlined in General Method 7 **Can beprepared from D-51 as outlined in General Method 7

The compounds from Table E above are named:

-   -   D-2: 5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-2-yl-ethyl)-heptanoic        acid methyl ester;    -   D-3: 5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-4-yl-ethyl)-heptanoic        acid methyl ester;    -   D-4: 5-Hydroxy-6-methyl-3-oxo-5-(2-thiazol-5-yl-ethyl)-heptanoic        acid methyl ester;    -   D-5:        5-Hydroxy-6-methyl-5-[2-(5-methyl-thiazol-2-yl)-ethyl]-3-oxo-heptanoic        acid methyl ester;    -   D-6:        5-Hydroxy-6-methyl-5-[2-(4-methyl-thiazol-2-yl)-ethyl]-3-oxo-heptanoic        acid methyl ester;    -   D-7:        5-Hydroxy-6-methyl-5-[2-(2-methyl-thiazol-4-yl)-ethyl]-3-oxo-heptanoic        acid methyl ester;    -   D-8:        5-Hydroxy-6-methyl-5-[2-(5-methyl-thiazol-4-yl)-ethyl]-3-oxo-heptanoic        acid methyl ester;    -   D-9:        5-Hydroxy-5-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-10:        5-Hydroxy-5-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-11:        5-Hydroxy-5-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-12:        5-Hydroxy-5-[2-(4-isopropyl-thiazol-2-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-13:        5-[2-(2-Acetylamino-thiazol-4-yl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-14:        5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-2-yl-ethyl)-heptanoic acid        methyl ester;    -   D-15:        5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-4-yl-ethyl)-heptanoic acid        methyl ester;    -   D-16:        5-Hydroxy-6-methyl-3-oxo-5-(2-pyridin-3-yl-ethyl)-heptanoic acid        methyl ester;    -   D-17: 5-(2-Furan-2-yl-ethyl)-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-18: 5-(2-Furan-3-yl-ethyl)-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-19:        5-Hydroxy-6-methyl-3-oxo-5-[2-(tetrahydro-furan-2-yl)-ethyl]-heptanoic        acid methyl ester;    -   D-20:        5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic        acid methyl ester;    -   D-21:        5-Hydroxy-6-methyl-3′-oxo-5-(2-thiophen-2-yl-ethyl)-heptanoic        acid methyl ester;    -   D-22:        5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-23:        5-{2-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-24:        5-{2-[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-25:        5-Hydroxy-5-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-26:        5-Hydroxy-5-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-27:        5-Hydroxy-5-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-28:        5-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-29:        5-[2-(2-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-30:        5-[2-(4-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-31:        5-Hydroxy-6-methyl-3-oxo-5-[2-(1-trityl-1H-pyrazol-3-yl)-ethyl]-heptanoic        acid methyl ester;    -   D-32:        5-Hydroxy-6-methyl-3-oxo-5-[2-(1H-pyrrol-3-yl)-ethyl]-heptanoic        acid methyl ester;    -   D-33:        5-Hydroxy-5-[2-(1H-imidazol-4-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-34:        5-Hydroxy-6-methyl-3-oxo-5-(2-pyrimidin-5-yl-ethyl)-heptanoic        acid methyl ester;    -   D-35:        5-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-36:        5-[2-(4-Cyano-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-37:        5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenyl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-38:        5-Hydroxy-5-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3′-oxo-heptanoic        acid methyl ester;    -   D-39:        5-Hydroxy-5-[2-(1H-indol-5-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-40:        5-Hydroxy-6-methyl-3-oxo-5-{2-[2-(2.2.2-trifluoro-acetylamino)-thiazol-4-yl]-ethyl}-heptanoic        acid methyl ester;    -   D-41:        5-Hydroxy-6-methyl-5-[2-(4-methyl-thiophen-3-yl)-ethyl]-3-oxo-heptanoic        acid methyl ester;    -   D-42:        5-Hydroxy-6-methyl-5-[2-(3-methyl-thiophen-2-yl)-ethyl]-3-oxo-heptanoic        acid methyl ester;    -   D-43:        5-{2-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-2-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-44:        5-Hydroxy-5-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-45:        5-[2-(2,6-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3′-oxo-heptanoic        acid methyl ester;    -   D-46:        5-[2-(3,5-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-47:        5-[2-(2,4-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-48:        5-[2-(3,4,5-Trifluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-49:        5-[2-(5-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-50:        5-[2-(2-Ethyl-5-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester;    -   D-51:        5-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoic        acid methyl ester; and    -   D-52:        5-Hydroxy-5-[2-(4-fluoro-2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoic        acid methyl ester.        General Method 8. Preparation of the Intermediate        4-Hydroxy-5,6-dihydro-pyran-2-ones

The aldol intermediate was dissolved in THF (1 volume) and treated with9 to 10 volumes of NaOH (0.1N-1.0N). The reaction was stirred from 1hour to 24 hours at room temperature. The base solution was extractedwith Et₂O and then cooled to 0° C. The mixture was acidified to pH 4 to5 using HCl (0.1N to 6N) or acetic acid. On occasion, the product couldbe isolated by filtration. Alternatively the acidified extracts wereextracted with EtOAc. The organic extracts were combined, dried (MgSO₄)and concentrated. Purification was accomplished by trituration from Et₂Oor flash chromatography.

EXAMPLE E-1

4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 8 usingthe crude aldol product isolated in Example D-1, 20 mL of f THF, and 200mL of 1.0N NaOH. The reaction mixture was stirred at room temperaturefor 2 hours, then poured over ice and acidified to pH 5.1. The solutionwas extracted with EtOAc, dried (MgSO₄), and concentrated. Purificationby silica gel chromatography, eluting with 5:95 MeOH:CH₂Cl₂, gave thetitle compound.

¹H NMR (DMSO-d₆): δ 0.87-0.90 (m, 6H), 1.82-1.96 (m, 2H), 2.07-2.18 (m,1H), 2.25 (s, 3H), 2.31 (d of ABX q, 1H), 2.60 (d of ABX q, 1H),2.74-2.81 (m, 2H), 4.96 (s, 1H), 8.78 (s, 1H), 11.39 (s, 1H).

The following dihydropyrones were prepared from the corresponding aldolproducts from Examples D-1 to D-51. The 4-hydroxy-dihydropyrones existin different forms depending upon the solvent.

TABLE F Preparation of Racemic 4-Hydroxy-Dihydropyrones

General Analytical Data Example Aryl R₁₀ Method (¹H NMR or MS) E-2

i-Propyl Gen. Method 8 MS (APCI): 268 (M + H) E-3

i-Propyl Gen. Method 8 MS (APCI): 268 (M + H) E-4

i-Propyl Gen. Method 8 MS (APCI): 268 (M + H) E-5

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-6

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-7

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-8

i-Propyl Gen. Method 8 MS (APCI): 282 (M + H) E-9

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-10

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-11

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-12

i-Propyl Gen. Method 8 MS (APCI): 310 (M + H) E-13

i-Propyl Gen. Method 8 MS (APCI): 325 (M + H) E-14

i-Propyl Gen. Method 8 MS (APCI): 262 (M + H) E-15

i-Propyl Gen. Method 8 (CDCl₃): δ 1.05(d, 6H), 1.7-1.9(m, 1H),2.0-2.2(m, 2H), 2.6-2.9(ABq, 2H), 2.7-2.8(m, 2H), 3.42(s, 2H), 7.05(d,2H), 8.5(d, 2H). E-16

i-Propyl Gen. Method 8 (CDCl₃): δ 1.00(d, 6H), 1.7-1.9(m, 1H),1.95-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.6-2.8(m, 2H), 3.40(s, 2H),7.15-7.25(m, 1H), 7.4-7.5(m, 1H), 8.4-8.5(s.m, 2H). E-17

i-Propyl Gen. Method 8 (CDCl₃): δ 1.1(dd, 6H), 1.7-1.9(m, 1H),2.0-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.7-2.9(m, 2H), 3.40(s, 2H), 6.0(m,1H), 6.30(m, 1H), 7.3(m, 1H). E-18

i-Propyl Gen. Method 8 (CDCl₃): δ 1.1(dd, 6H), 1.7-1.9(m, 1H),1.95-2.2(m, 2H), 2.5-2.7(m, 2H), 2.6-2.8(ABq, 2H), 3.40(s, 2H), 6.25(s,1H), 7.1(m, 1H), 7.18(m, 1H). E-19

i-Propyl Gen. Method 8 (CDCl₃): δ 0.8-2.2 (m, 15H), 2.65 (AB q, 2H),3.40(ABq, 2H), 3.60-3.90(m, 3H). E-20

i-Propyl Gen. Method 8 Mp 140-142.5° C. E-21

i-Propyl Gen. Method 8 (CDCl₃): δ 1.05 (d, 6H), 1.8-2.0(m, 1H),2.0-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.9-3.1(m, 2H), 3.40(s, 2H), 6.8(m,1H), 6.9(m, 1H), 7.15(m, 1H). E-22

i-Propyl Gen. Method 7 then Gen. Method 8 (CDCl₃): δ 1.1(d, 6H),1.8-2.0(m, 1H), 2.0-2.2(m, 2H), 2.6-2.8(ABq, 2H), 2.8-3.0(m, 2H),3.40(s, 2H), 4.75(s, 2H), 6.65(d, 1H), 6.8(d, 1H). E-23

i-Propyl Gen. Method 7 then Gen. Method 8 (CDCl₃): δ 1.0(dd, 6H),1.7-1.9(m, 2H), 2.0-2.2(m, 2H), 2.6-2.8(m, Abq, 4H), 3.40(s, 2H), 4.8(d,2H), 6.8(s, 1H), 6.9(s, 1H). E-24

i-Propyl Gen. Method 7 then Gen. Method 8 MS (APCI): 295 (M − H) E-25

i-Propyl Gen. Method 8 (DMSO-d₆): δ 0.90 (d, 3H), 0.92(d, 3H),1.73-1.90(m, 2H), 2.10-2.19(m, 4H), 2.28(d of ABX q, 1H), 2.58-2.65(m,3H), 4.97(s, 1H), 6.92-6.98(m, 2H), 7.08-7.15(m, 1H), 11.39(bs, 1H).E-26

i-Propyl Gen. Method 8 (DMSO-d₆): δ 0.89 (d, 3H), 0.91(d, 3H),1.81-1.95(m, 2H), 2.08-2.17(m, 1H), 2.28(d of ABX q, 1H), 2.58-2.64(m,3H), 4.96(s, 1H), 7.07-7.14(m, 2H), 7.19-7.28(m, 2H), 11.37(bs, 1H).E-27

i-Propyl Gen. Method 8 (DMSO-d₆): δ 0.88 (d, 3H), 0.90(d, 3H),1.82-1.91(m, 2H), 2.05-2.14(m, 1H), 2.32(d of ABX q, 1H), 2.54-2.62(m,3H), 4.96(s, 1H), 7.04-7.11(m, 2H), 7.18-7.22(m, 2H), 11.35(bs, 1H).E-28

i-Propyl Gen. Method 8 MS (APCI): 250 (M) E-29

i-Propyl Gen. Method 8 MS (APCI): 250(M + H) E-30

i-Propyl Gen. Method 8 MS (APCI): 493(M + H) E-31

i-Propyl Gen. Method 8 MS (APCI): 263(M + H) E-32

i-Propyl Gen. Method 8 MS (APCI): 278(M + H) E-33

i-Propyl Gen. Method 8 MS (APCI): 286(M + H) E-34

i-Propyl Gen. Method 8 MS (APCI): 290 (M) E-35

i-Propyl 08/883,743 E-36

Cyclopentyl E-37

Cyclohexyl E-38

i-Propyl E-39

Cyclopentyl E-40

Cyclohexyl E-41

i-Propyl E-42

Cyclopentyl From 08/883,743 E-43

Cyclohexyl From 08/883,743 E-44

i-Propyl From 08/883,743 E-45

Cyclopentyl From 08/883,743 E-46

Cyclohexyl From 08/883,743 E-47

i-Propyl Gen. Method 8 MS (APCI): 300(M + H) E-48

i-Propyl Gen. Method 8 MS (APCI): 379(M + H) E-49

i-Propyl Gen. Method 8 MS (APCI): 281(M + H) E-50

i-Propyl Gen. Method 8 MS (APCI): 281(M + H) E-51

i-Propyl Gen. Method 8 (CDCl₃): δ 1.02-1.06 (dd, 6H), 1.80- 2.00(m, 1H),2.05-2.25(m, 2H), 2.61-2.79(ABq, 2H), 2.85-3.05(m, 2H), 3.34-3.52(AB q,2H), 4.60(d, 2H), 6.97(d, 1H), 7.10(d, 1H). E-52

i-Propyl Gen. Method 8 (CDCl₃) δ 0.88(d, 3H), 0.91(d, 3H), 1.74-1.94(m,2H), 2.10-2.19(m, 1H), 2.28(d of ABX q, 1 H), 2.58-2.65(m, 3 H), 4.97(s,1H), 6.92-6.98(m, 2H), 7.08-7.15(m, 1H), 11.39(bs, 1H) E-53

i-Propyl Gen. Method 8 (CDCl₃) δ 0.88(d, 3 H), 0.91(d, 3H), 1.87-1.93(m,2H), 2.04-2.13(m, 1H), 2.33(d of ABX q, 1 H), 2.60-2.69(m, 3 H), 4.96(s,1H), 7.00-7.04(m, 3H), 11.35(bs, 1H) E-54

i-Propyl Gen. Method 8 (DMSO) δ 0.89(d, 3 H), 0.91(d, 3H), 1.77-1.94(m,2H), 2.07-2.16(m, 1H), 2.29(d of ABX q, 1H), 2.57-2.63(m, 3H), 4.95(s,1H), 6.95-7.01(m, 1H), 7.11-7.19(m, 1H), 7.27-7.35(m, 1H), 11.36(bs, 1H)E-55

i-Propyl Gen. Method 8 (CDCl₃) δ 0.87(d, 3H), 0.89(d, 3H), 1.86-1.92(m,2H), 2.01-2.15(m, 1H), 2.34(d of ABX q, 1H), 2.53-2.61(m, 3H), 4.94(s,1H), 7.15-7.24(m, 2H), 11.36(bs, 1H). E-56

i-Propyl Gen. Method 8 (DMSO) δ 0.89 (d, 3 H), 0.91(d, 3H), 1.77-1.85(m,2H), 2.08-2.16(m+s, 4H), 2.29(d of ABX q, 1 H), 2.53-2.64(m, 3 H),4.96(s, 1H), 6.84-6.96(m, 2H), 7.10-7.15(m, 1H), 11.36(bs, 1H) E-57

i-Propyl Gen. Method 8 (DMSO) δ 0.89(d, 3 H), 0.91(d, 3H), 1.09 (t, 3H),1.80-1.87(m, 2H), 2.08-2.17(m, 1 H), 2.28(d of ABX q, 1H), 2.47-2.51(m,partially obscured by DMSO, 2H), 2.54- 2.64(m, 3H), 4.96(s, 1H),6.88-6.95(m, 2 H), 7.15-7.18(m, 1 H), 11.38(bs, 1H). E-58

i-Propyl Gen. Method 8 E-59

i-Propyl Gen. Method 7 (from E-58) (DMSO) δ 0.95(d, 3 H), 0.93(d, 3H),1.84-1.94(m, 2H), 2.14-2.26(m, 1H), 2.35(d of ABX q, 1H), 2.53-2.62(m,partially obscured by DMSO, 2H), 2.66(d of ABX q, 1H), 4.52 (s, 2H),5.03(s, 1H), # 5.32(bs, 1H), 6.99- 7.05(m, 1H), 7.15- 7.22(m, 2H), 11.42(bs, 1H)

The compounds from Table F above are named:

-   -   E-2:        4-Hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-3:        4-Hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-4:        4-Hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-5:        4-Hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-6:        4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-7:        4-Hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-8:        4-Hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-9:        4-Hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-10:        4-Hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-11:        4-Hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-12:        4-Hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-13:        N-{4-[2-(4-Hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide;    -   E-14:        4-Hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-15:        4-Hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-16:        4-Hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-17:        6-(2-Furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-18:        6-(2-Furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-19:        4-Hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-5,6-dihydro-pyran-2-one;    -   E-20:        4-Hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-21:        4-Hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-22:        4-Hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-23:        4-Hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-24:        4-Hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-25:        6-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-26:        6-[2-(2-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-27:        6-[2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-28:        4-Hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-29:        4-Hydroxy-6-isopropyl-6-[2-(1H-pyrrol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-30:        4-Hydroxy-6-isopropyl-6-[2-(1-trityl-1H-imidazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-31:        4-Hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   E-32:        6-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-33:        4-[2-(4-Hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-benzonitrile;    -   E-34:        4-Hydroxy-6-isopropyl-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-47:        4-Hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-48:        2,2,2-Trifluoro-N-{4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide;    -   E-49:        4-Hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-50:        4-Hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   E-51:        4-Hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-52:        6-[2-(2,6-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-53:        6-[2-(3,5-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-54:        6-[2-(2,4-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-55:        6-[2-(3,4,5-Trifluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-56:        6-[2-(5-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-57:        6-[2-(2-Ethyl-5-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   E-58:        6-{2-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-fluoro-phenyl]-ethyl}-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;        and    -   E-59:        6-[2-(4-Fluoro-2-hydroxymethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.        Alternate Synthesis of 4-Hydroxy-5,6-dihydro-pyran-2-ones via        β-Hydroxyesters.        General Method 9. Preparation of β-Hydroxyesters from Ketones        (Table D) or Enones (Table B)

Diisopropylamine (1.25-1.4 equiv.) was cooled to −10° C. and treatedwith nBuLi (1.25 equiv.) over 10 to 20 minutes. The solution was stirredfor 15 to 45 minutes at −10° C. and then cooled to −60° C. to −78° C.The desired acetate (1.25 equiv.) was dissolved in THF and addeddropwise to the LDA solution over 30 to 90 minutes. When addition wascomplete, the reaction mixture was stirred at −78° C. to −40° C. foranother 30 to 90 minutes. The appropriate ketone (from Examples C-1 toC-39) or enone (from Examples B-1 to B-30) was dissolved in THF andadded over 15 to 30 minutes. The reaction mixture was warmed to roomtemperature and stirred for 3 to 18 hours. The solution was poured into1N HCl:ice; the product was extracted into EtOAc, dried (MgSO₄), andconcentrated. The product could be purified via chromatography orrecrystallization.

EXAMPLE F-1

3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid tert-butylester

The title compound was prepared as described in General Method 9 usingt-butyl acetate (42.6 mmol), diisopropyl amine (42.6 mmol), nBuLi (42.6mmol), 4-methyl-1-thiophen-3-yl-pentan-3-one (Example C-5; 21.3 mmol),and THF (100 mL). The title compound was purified by flashchromatography over silica gel eluting with hexane:EtOAc 97:3. ¹NMR(CDCl₃): δ 0.95 (dd, 6H), 1.47 (s, 9H), 1.7-2.0 (m, 3H), 2.36-2.54 (ABq, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m, 1H).

The following hydroxyesters were prepared in similar fashion from theanalogous ketones from Examples C-1 to C-57 or enones from Examples B-1to B-36:

TABLE G Preparation of Hydroxyesters

Analytical Data Example R₁₁ R₁₂ (¹H NMR or MS) F-2

CH₂Ph (CDCl₃): δ 0.94(d, 3H), 0.96(d, 3H), 1.79-1.88(m, 1H), 2.71(s,2H), 4.00(br s, 1H), 5.07(d, 1H), 5.14(d, 1H), 6.19(d, 1H), 6.58(d, 1H),6.90-6.70(m, 2H), 7.06-7.09(m, 1H), 7.24-7.29(m, 5H), 7.36-7.38(m, 1H).F-3

CH₂Ph F-4

CH₂Ph MS(APCI): 393(M + H) F-5

CH₂Ph MS(APCI): 393(M + H) F-6

CH₂Ph MS(APCI): 393(M + H) F-7

CH₂Ph MS(APCI): 411(M + H) F-8

CH₂Ph MS(APCI): 411(M + H) F-9

CMe₃ MS(APCI): 323(M + H) F-10

CMe₃ (CDCl₃): δ 0.95(d, 3H), 0.97(d, 3H), 1.48(s, 9H), 1.75-1.86(m, 2H),1.88-1.96(m, 1H), 2.40(d, 1H), 2.52(d, 1H), 2.63-2.73(m, 2H), 3.92(s,1H), 7.16-7.21(m, 3H), 7.26-7.31(m, 2H). F-11

CH₂Ph MS(APCI): 326(M + H) F-12

CH₂Ph (CDCl₃): δ 0.95(d, 3H), 0.96(d, 3H), 1.76-1.88(m, 1H), 2.71(s,2H), 3.98(bs, 1H), 5.05(d, 1H), 5.13(d, 1H), 6.10(d, 1H), 6.57(d, 1H),6.95-7.03(m, 2H), 7.23-7.31(m, 7H). F-13

Et (CDCl₃): δ 0.00(s, 9H), 0.83(s, 6H), 0.99(d, 6H), 1.3(t, 3H),1.7-2.0(m, 3H), 2.50(dd, 2H), 2.60(t, 2H), 3.71(s, 1H), 4.19(q, 2H),4.66(s, 2H), 6.91(d, 1H), 7.2(d, 1H). F-14

CMe₃ (CDCl₃): δ 0.93-0.97(t, 6H), 1.47(s, 9H), 1.6-1.80(m, 2H),1.91-1.95 (m, 1H), 2.37(s, 3H), 2.37-2.40(d, 1H), 2.48-2.51 (d, 1H),2.56-2.51(m, 2H), 3.92(s, 1H), 6.80(d, 1H), 6.99(d, 1H). F-15

CH₂Ph F-16

CH₂Ph (CDCl₃) δ 0.93(d, 3H), 0.95(d, 3H), 1.77-1.87(m, 1H), 2.70(s, 2H),4.00(s, 1H), 5.06(d, 1H), 5.15(d, 1H), 6.18(d, 1H), 6.52(d, 1H),6.64-6.71(m, 1H), 6.75- 7.82(m, 2H), 7.24-7.38(m, 2H). F-17

CMe₃ (CDCl₃) δ 0.94(d, 3H), 0.96(d, 3H), 1.46(s, 9H), 1.60-1.75(m, 2H),1.89-1.97 *m, 1H), 2.309(s, 3H), 2.39 (d, 1H), 2.50(d, 1H), 2.56-2.67(m, 2H), 3.97(s, 1H), 6.77-6.86(m, 2H), 7.04-7.08 (m, 1H).

The compounds of Table G above are named:

-   -   F-2: 5-(3-Fluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic acid        benzyl ester;    -   F-3: 5-(3,4-Difluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic        acid benzyl ester;    -   F-4:        3-Hydroxy-3-isopropyl-5-(2-trifluoromethyl-phenyl)-pent-4-enoic        acid benzyl ester;    -   F-5:        3-Hydroxy-3-isopropyl-5-(3-trifluoromethyl-phenyl)-pent-4-enoic        acid benzyl ester;    -   F-6:        3-Hydroxy-3-isopropyl-5-(4-trifluoromethyl-phenyl)-pent-4-enoic        acid benzyl ester;    -   F-7:        5-(3-Fluoro-5-trifluoromethyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic        acid benzyl ester;    -   F-8:        5-(4-Fluoro-3-trifluoromethyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic        acid benzyl ester;    -   F-9:        3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-4-methyl-pentanoic        acid tert-butyl ester;    -   F-10: 3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acid        tert-butyl ester;    -   F-11: 3-Hydroxy-3-isopropyl-5-phenyl-3-pent-4-enoic acid benzyl        ester;    -   F-12: 5-(4-Fluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic        acid benzyl ester;    -   F-13:        3-{2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-3-hydroxy-4-methyl-pentanoic        acid ethyl ester;    -   F-14:        3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoic        acid tert-butyl ester;    -   F-15:        5-(3-Fluoro-2-methyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic        acid benzyl ester;    -   F-16: 5-(3,5-Difluoro-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic        acid benzyl ester; and    -   F-17:        5-(4-Fluoro-2-methyl-phenyl)-3-hydroxy-3-isopropyl-pent-4-enoic        acid tert-butyl ester.        Separation of β-Hydroxy Ester Enantiomers via Chiral HPLC

EXAMPLE F-1 (S)

(S)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acidtert-butyl ester

The title compound was prepared by resolution on a Chiralpak AD columneluting with 1:99 isopropanol:hexane to afford both enantiomers of3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid tert-butylester. The S enantiomer eluted first.

¹H NMR (CDCl₃): δ 0.95 (dd 6H), 1.47 (s, 9H), 1.7-2.00 (m, 3H),2.36-2.54 (AB q, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m,1H).

EXAMPLE F-1 (R)

(R)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acidtert-butyl ester

The title compound was prepared as described above via resolution ofCompound F-9 on a Chiralpak AD column eluting with 1:99isopropanol:hexane to afford both enantiomers of3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid tert-butylester. The R enantiomer eluted second.

¹H NMR (CDCl₃): δ 0.95 (dd, 6H), 1.47 (s, 9H), 1.7-2.00 (m, 3H),2.36-2.54 (AB q, 2H), 2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m,1H).

EXAMPLE F-9 (S)

(S)-3-Hydroxy-4-methyl-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-pentanoicacid tert-butyl ester

The title compound was prepared by resolution of Compound F-9 on aChiralpak AD column eluting with isopropanol:hexane (1:99) to affordboth enantiomers of3-hydroxy-4-methyl-3-[2-(2-hydroxymethyl-phenyl)-ethyl)-pentanoic acidtert-butyl ester. MS (APCI): 323 (M+H).

EXAMPLE F-14 (S)

(S)-3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoicacid tert-butyl ester

The title compound was prepared by resolution on a Chiralpak AD columneluting with 0.75:0.25:99 ethanol:isopropanol:hexane to afford bothenantiomers of3-hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoic acidtert-butyl ester. The S enantiomer eluted first.

¹H NMR (CDCl₃): δ 0.93-0.97 (t, 6H), 1.47 (s, 9H), 1.6-1.80 (m, 2H),1.91-1.95 (m, 1H), 2.37 (s, 3H), 2.37-2.40 (d, 1H), 2.48-2.51 (d, 1H),2.56-2.61 (m, 2H), 3.92 (s, 1H), 6.80 (d, 1H), 6.99 (d, 1H).

General Method 10. Preparation of β-Hydroxyacids

The appropriate β-hydroxyester (1 equiv.) was dissolved in EtOH andtreated with 1.4 to 2.0 equivalents of an alkoxide (KOH or LiOH). Themixture was stirred at room temperature or heated to reflux for 4 to 18hours. The solution was concentrated to dryness, and the residue waspartitioned between H₂O and Et₂O. The aqueous layer was separated,acidified with 1N HCl, and extracted with Et₂O. The solution was dried(MgSO₄) and concentrated.

Alternatively, the benzyl esters (compounds F-2 through F-8 andcompounds F-11 and F-12) were hydrogenated as described in GeneralMethod 3 to give the corresponding acid.

EXAMPLE G-1 (S)

(S)-3-Hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid

The title compound was prepared as described in General Method 10 using(S)-3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acidtert-butyl ester (Example F-1 (S); 8 mmol), LiOH (16 mmol), H₂O (5 mL),and MeOH (15 mL).

¹NMR (CDCl₃): δ 0.98 (t, 6H), 1.8-2.0 (m, 3H), 2.50-2.70 (Ab q, 2H),2.6-2.8 (m, 2H), 6.93-6.95 (m, 2H), 7.23-7.25 (m, 1H).

The following β-hydroxyacids were prepared from the correspondingesters, either by hydrolysis (General Method 10) or hydrogenolysis (asoutlined in General Method 3) as noted:

TABLE H Synthesis of β-hydroxyacids

Analytical Data Example R₁₃ General Method Chirality (¹H NMR or MS) G-1(R)

Gen. Method 10 R (CDCl₃): δ 0.98(t, 6H), 1.8-2.0(m, 3H), 2.50-2.70(AB q,2H), 2.6-2.8(m, 2H), 6.93-6.95(m, 2H), 7.23-7.25(m, 1H). G-1

Gen. Method 10 ± (CDCl₃): δ 0.92-0.95(m, 6H), 1.78-2.02(m, 3H),2.49-2.76(m, 4H), 6.91 (m, 2H), 7.22(m, 1H). G-2

Gen. Method 3 ± (CDCl₃): δ 0.95-1.00(m, 6H), 1.71-2.03(m, 3H),2.49-2.56(m, 1H), 2.62-2.73(m, 3H), 3.75-3.79(m, 1H), 6.84-6.91(m, 2H),6.96(d, 1H), 7.18-7.27(m, 1H). G-3

Gen. Method 3 ± (CDCl₃): δ 0.94-0.99(m, 6H), 1.78-1.89(m, 2H),1.92-2.01(m, 1H), 2.52(d, 1H), 2.61-2.70 (m, 3H), 3.75-3.79(m, 1H),6.85-6.91(m, 1H), 6.94-7.09(m, 2H). G-4

Gen. Method 3 ± MS(APCI): 303(M − H) G-5

Gen. Method 3 ± MS(APCI): 303(M − H) G-6

Gen. Method 3 ± MS(APCI): 607(M − H) G-7

Gen. Method 3 ± MS(APCI): 321(M − H) G-8

Gen. Method 3 ± MS(APCI): 321(M − H) G-9

Gen. Method 10 S MS(APCI): 266(M) Rotation: −3.8° (c = 2.0, EtOH) G-10

Gen. Method 10 (using F-10) or Gen. Method 3 (using F-11) ± (CDCl₃): δ0.97(d, 3H), 0.99(d, 3H), 1.80-1.93(m, 2H), 1.95-2.05(m, 2H), 2.56 (d,1H), 2.65-2.74(m, 3H), 7.17-7.21(m, 3H), 7.26-7.32(m, 2H). G-11

Gen. Method 3 ± (CDCl₃): δ 0.96(d, 3H), 0.99(d, 3H), 1.76-1.89(m, 2H),1.91-2.05(m, 1H), 2.55(d, 1H), 2.63-2.70 (m, 3H), 3.74-3.78(m, 1H),6.93-6.91(m, 2H), 7.11-7.16(m, 2H). G-12

Gen. Method 10 ± MS(APCI): 385(M − H) G-13

Gen. Method 10 S MS(APCI): 255 (M − H) G-14

Gen. Method 3 ± (CDCl₃) δ 0.97(d, 3H), 0.99(d, 3H), 1.66- 1.86(m, 2H),1.96- 2.05(m, 1H), 2.21(d, 3H), 2.59(d, 1H), 2.65-2.73(m, 3H),6.84-6.93(m, 2H), 7.03-6.10(m, 1H). G-15

Gen. Method 10 ± (CDCl₃) δ 0.96(d, 3H), 0.98(d, 3H), 1.81-1.86 (m, 2H),1.87-2.01(m, 1H), 2.53(d, 1H), 2.64-2.78(m, 3H), 3.74-3.78(m, 1H),6.59-6.67(m, 1H), 6.69-6.74(m, 2H). G-16

Gen. Method 10 ±

The compounds of Table H above are named:

-   -   G-2: 3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid;    -   G-3:        3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid;    -   G-4:        3-Hydroxy-4-methyl-3-[2-(2-trifluoromethyl-phenyl)-ethyl]-pentanoic        acid;    -   G-5:        3-Hydroxy-4-methyl-3-[2-(3-trifluoromethyl-phenyl)-ethyl]-pentanoic        acid;    -   G-6:        3-Hydroxy-4-methyl-3-[2-(4-trifluoromethyl-phenyl)-ethyl]-pentanoic        acid;    -   G-7:        3-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid;    -   G-8:        3-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid;    -   G-9:        (S)-3-Hydroxy-3-[2-(2-hydroxymethyl-phenyl)-ethyl]-4-methyl-pentanoic        acid;    -   G-10: 3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acid;    -   G-11: 3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid;    -   G-12:        3-{2-[4-(tert-Butyl-dimethyl-silanyloxy-methyl)-thiophen-3-yl]-ethyl}-3-hydroxy-4-methyl-pentanoic        acid;    -   G-13:        3-Hydroxy-4-methyl-3-[2-(2-methyl-thiophen-3-yl)-ethyl]-pentanoic        acid;    -   G-14:        3-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid;    -   G-15:        3-[2-(3,5-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid; and    -   G-16:        3-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic        acid.        Resolution of Racemic β-hydroxyacids Enantiomers

EXAMPLE G-2 (R)

(R)-3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid

Racemic compound G-2 (42.0 g, 165 mmol) from Table H was dissolved in410 mL EtOAc and treated with (S)-α-methylbenzylamine (10.01 g, 82.58mmol). The resulting slurry was placed on a steam bath and heated toreflux to dissolve the solids completely. The solution was allowed tocool to room temperature slowly overnight. The flask was then cooled to5° C., and the solids were filtered and washed with cold EtOAc and Et₂O.The product was recrystallized from hot EtOAc (110 mL) on a steam bath,and then cooled slowly to room temperature overnight. The flask was thencooled (5° C.); the solids were filtered and washed with cold EtOAcfollowed by Et₂O to yield the desired compound. HPLC analysis ofisolated solid (as the free acid): (AD chiralpak column, 1 mL/min.,97.5% Hexanes:2.5% IPA+0.1% TFA)

-   -   retention time: 19.60 min. (95.3%) 22.67 min. (4.7%)

EXAMPLE G-2 (S)

(S)-3-[2-(3-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid

A second solid was isolated from the mother liquor from Example G-2 (R)after the solution was allowed to stand for 48 hours. The mixture wascooled to 0° C. in ice bath for several hours. The solid was filteredoff and washed with cold EtOAc followed by Et₂O. HPLC analysis ofisolated solid (as the free acid): (AD chiralpak column, 1 mL/min.,97.5% Hexanes:2.5% IPA+0.1% TFA)

-   -   retention time: 18.11 min. (11.76%) 19.28 min. (88.24%).

The isolated solid was recrystallized from hot EtOAc (˜100 mL) on asteam bath and cooled slowly to room temperature overnight. The mixturethen was cooled in an ice bath for 2 hours. The resulting solids werefiltered and washed with cold EtOAc followed by Et₂O to give the desiredenantiomer. The free acid was obtained by treating the salt with 1N HClfollowed by extraction with EtOAc. The organic phased was washed withbrine, dried (MgSO₄), filtered and concentrated to afford the resolvedβ-hydroxy acid. HPLC analysis of isolated solid (as the free acid): (ADchiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA+0.1% TFA)

-   -   retention time: 18.20 min. (3.4%) 19.42 min. (96.6%)

EXAMPLE G-3 (R)

(R)-3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid

Compound G-3 (16.0 g, 58.8 mmol) from Table H was dissolved in 150 mLEtOAc and treated with (S)-α-methylbenzylamine (3.77 g, 31.14 mmol). Thethick suspension that resulted was placed on a steam bath and heated toreflux. Additional EtOAc (240 mL) was added, followed by hot isopropanol(approximately 80 mL), until the solids dissolved. The solution wasallowed to cool to room temperature slowly overnight. The mixture wasthen cooled to approximately 0° C. The resulting solids were filteredand washed with cold EtOAc followed by Et₂O to yield the desiredenantiomer. HPLC analysis of isolated solid (as the free acid): (ADchiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA+0.1% TFA)

-   -   retention time: 23.80 min. (7.7%) 25.10 min. (92.3%).

The isolated solid was dissolved in hot IPA (120 mL) and EtOAc (600 mL)on a steam bath and then cooled slowly to room temperature overnight.The flask was cooled in an ice bath for several hours and then filtered.The solids were washed with cold EtOAc followed by Et₂O to yield thepure stereoisomer. The free acid was obtained by treating the salt with1N HCl followed by extraction with EtOAc. The organic phased was washedwith brine, dried (MgSO₄), filtered and concentrated to afford theresolved β-hydroxy acid. HPLC analysis of isolated solid (as the freeacid): (AD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA+0.1% TFA)

-   -   retention time: 25.90 min. (>99%).

EXAMPLE G-3 (S)

(S)-3-[2-(3,4-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid

The mother liquor from the isolation of diastereomaric salt G-3 (R) wastreated with 1N HCl and extracted with EtOAc. The organic phased waswashed with brine, dried (MgSO₄), filtered and concentrated to liberatecompound G-3. HPLC analysis indicated the isolated material was 78%(S):22% (R) based on comparison with previously isolated solid(diastereomaric salt G-3 (R)). β-Hydroxy acid G-3 (9.75 g, 35.8 mmol)was dissolved in 100 mL EtOAc and treated with (R)-α-methylbenzylamine(3.25 g, 26.86 mmol). The resulting thick suspension was placed on asteam bath and heated to reflux. Additional EtOAc (50 mL) was added,followed by hot IPA (100 mL), a little at a time until the solidsdissolved. The solution was allowed to cool to room temperatureovernight. The mixture was then cooled to 0° C. in an ice bath. Theresulting solids were filtered and washed with cold EtOAc followed byEt₂O. The free acid was obtained by treating the salt with 1N HClfollowed by extraction with EtOAc. The organic phased was washed withbrine, dried (MgSO₄), filtered and concentrated to afford the resolvedβ-hydroxy acid. HPLC analysis of isolated material (as the free acid):(AD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA+0.1% TFA)

-   -   retention time: 22.06 min. (96.9%) 24.34 min. (3.1%).

Example G-10 (S)

(S)-3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acid

Compound G-10 (15.0 g, 63.48 mmol) was dissolved in 155 mL EtOAc andtreated with (S)-α-methylbenzylamine (4.23 g, 34.91 mmol). The resultingslurry was placed on a steam bath and heated to reflux at which allsolids dissolved. The solution allowed to cool to room temperatureslowly overnight, then cooled to −20° C. Cold EtOAc was added, and thesolids were filtered and washed with cold EtOAc and Et₂O to yield thetitle compound. The free acid was obtained by treating the salt with 1NHCl followed by extraction with EtOAc. The organic phased was washedwith brine, dried (MgSO₄), filtered and concentrated to afford theresolved β-hydroxy acid. HPLC analysis of isolated solid (as the freeacid): (OD chiralpak column, 1 mL/min., 97.5% Hexanes:2.5% IPA:+0.1%Formic acid)

-   -   retention time: 20.67 min. (4.4%) 22.24 min. (95.6%).

EXAMPLE G-10 (R)

(R)-3-Hydroxy-4-methyl-3-(2-phenyl-ethyl)-pentanoic acid

The mother liquor from the isolation of diastereomeric salt G-10 (S) wastreated with 1N HCl and extracted with EtOAc. The organic phase waswashed with brine, dried (MgSO₄), filtered and concentrated to liberatethe free β-hydroxy acid. HPLC analysis indicated the isolated materialwas 73% (R):27% (S). β-Hydroxy acid G-10 (1 equiv.) was dissolved in 600mL EtOAc and treated with (R)-α-methylbenzylamine (0.74 equiv.). Theresulting suspension was placed on a steam bath and heated to reflux.The solution was allowed to cool to room temperature slowly and thencooled to 0° C. in an ice bath. The resulting solids were filtered offand washed with cold EtOAc followed by Et₂O to yield the title compound.The free acid was obtained by treating the salt with 1N HCl followed byextraction with EtOAc. The organic phased was washed with brine, dried(MgSO₄), filtered and concentrated to afford the resolved β-hydroxyacid. HPLC analysis of isolated solid (as the free acid): (OD chiralpakcolumn, 1 mL/min., 97.5% Hexanes:2.5% IPA:+0.1% Formic acid)

-   -   retention time: 21.86 min. (95.6%) 23.75 min. (4.4%).

EXAMPLE G-11 (R)

(R)-3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid

Compound G-11 (37.1 g, 146 mmol) was dissolved in 375 mL EtOAc andtreated with (S)-α-methylbenzylamine (4.23 g, 34.9 mmol). The resultingslurry was heated to reflux, diluted with an additional 50 to 100 mLEtOAc, and treated with hot isopropanol until the solids had completelydissolved. The solution was allowed to cool to room temperature slowlyand then cooled to 0° C. in an ice bath for ˜1 hour. Cold EtOAc wasadded; the solids were filtered off and washed with cold EtOAc and Et₂Oto yield the title compound. HPLC analysis of isolated solid (as thefree acid): (AS chiralpak column, 1 mL/min., 98% Hexanes:2% IPA:+0.1%Formic acid)

-   -   retention time: 16.81 min. (7.52%) 21.42 min. (92.48%).

The isolated solid and 450 mL EtOAc was heated to reflux and treatedwith hot isopropanol until the solids dissolved. The solution wasallowed to cool to room temperature slowly overnight. The flask was thencooled to −10 to −15° C. and treated with cold EtOAc. The solids werefiltered off and washed with cold EtOAc and Et₂O to yield the titlecompound. The free acid was obtained by treating the salt with 1N HClfollowed by extraction with EtOAc. The organic phased was washed withbrine, dried (MgSO₄), filtered and concentrated to afford the resolvedβ-hydroxy acid. HPLC analysis of isolated solid (as the free acid): (ASchiralpak column, 1 mL/min., 98% Hexanes:2% IPA:+0.1% Formic acid)

-   -   retention time: 16.74 min. (1.19%) 20.95 min. (98.81%).

EXAMPLE G-11 (S)

(S)-3-[2-(4-Fluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid

The mother liquors from the isolation of the G-11 (R) enantiomer werecombined, treated with 1N HCl and extracted with EtOAc. The organicphase was washed with brine, dried (MgSO₄), filtered and concentrated toliberate the free β-hydroxy acid. HPLC analysis indicated the isolatedmaterial was 79% (S):21% (R). β-Hydroxy acid G-11 (22.6 g, 89.0 mmol)was dissolved in 250 mL EtOAc and treated with (R)-α-methylbenzylamine(9.17 g, 75.64 mmol). The resulting mixture was placed on a steam bath,heated to reflux, diluted with additional ˜100 mL EtOAc, and treatedwith hot isopropanol until solids completely dissolved. The solution wasallowed to cool to room temperature slowly overnight and then cooled to−10 to −15° C. Cold EtOAc was added; the solids were filtered off andwashed with cold EtOAc and Et₂O to yield the title compound. The freeacid was obtained by treating the salt with 1N HCl followed byextraction with EtOAc. The organic phased was washed with brine, dried(MgSO₄), filtered and concentrated to afford the resolved β-hydroxyacid. HPLC analysis of isolated solid (as the free acid): (AS chiralpakcolumn, 1 mL/min., 98% Hexanes:2% IPA:+0.1% Formic acid)

-   -   retention time: 16.61 min. (96.17%) 20.77 min. (3.83%).

EXAMPLE G-14 (S)

(S)-3-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid

Compound G-14 (28.3 g, 105 mmol) was dissolved in 270 mL EtOAc andtreated with (R)-α-methylbenzylamine (6.52 g, 53.8 mmol). No precipitateformed. After 2 hours the solvent was evaporated. To the resultingresidue was added 200 mL hexanes, and the flask was refluxed on a steambath until the solids dissolved. Et₂O (20 mL) was added and the solutionallowed to cool to room temperature slowly overnight. The resultingsolids were filtered off and washed with cold hexanes/Et₂O. HPLCanalysis of isolated solid (as the free acid): (AS chiralpak column, 0.8mL/min., 98% Hexanes/2% IPA/+0.1% Formic acid).

-   -   retention time: 16.38 min. (80.76%) 22.67 min. (19.24%)        The isolated solids, Et₂O (100 mL), and hexanes (200 mL) were        heated to reflux on a steam bath. EtOAc was added until all        solids dissolved (approximately 150 mL). An additional 200 mL of        hexanes were added, and the mixture was brought back to reflux        and then allowed to cool slowly to room temperature overnight.        The flask was then cooled to approx. 5° C. for 2 hours. The        resulting solids were filtered and washed with cold Et₂O to        yield the title compound. HPLC analysis of isolated solid (as        the free acid): (AS chiralpak column, 1 mL/min., 98% Hexanes/2%        IPA/+0.1% Formic acid).    -   retention time: 12.12 min. (94.8%) 24.10 min. (5.2%)

EXAMPLE G-15 (S)

(S)-3-[2-(3,5-Difluoro-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid

Compound G-15 (24.6 g, 90.5 mmol) was dissolved in 235 mL EtOAc andtreated with (R)-α-methylbenzylamine (6.03 g, 49.8 mmol). The resultingslurry was placed on a steam bath and heated to reflux until all solidsdissolved. The solution was allowed to cool and hexanes were added(approximately 100 mL). The solution was returned to reflux, the steamturned off, and the mixture allowed to cool to room temperatureovernight. The flask was then cooled to approx. 5° C. for 1 hour. Theresulting solids were filtered and washed with cold Et₂O. HPLC analysisof isolated solid (as the free acid): (AS chiralpak column, 1.0 mL/min.,98% Hexanes/2% IPA/+0.1% Formic acid).

-   -   retention time: 12.51 min. (92.3%) 14.83 min. (7.7%)

The solids were suspended in EtOAc (approximately 300 mL) and heated toreflux on a steam bath. When the solids did not dissolve, isopropanol(approximately 20 mL) was added gradually until the material completelydissolved. An additional 100 mL of EtOAc was added; the mixture wasbrought back to reflux and then allowed to cool to room temperatureovernight. The flask was then cooled to approx. 5° C. for 2 hours. Theresulting solids were filtered and washed with cold Et₂O to yield thetitle compound. HPLC analysis of isolated solid (as the free acid): (ASchiralpak column, 1 mL/min., 98% Hexanes/2% IPA/+0.1% Formic acid).

-   -   retention time: 12.65 min. (98.0%) 15.10 min. (2.0%)

EXAMPLE G-16 (S)

(S)-3-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoicacid

Compound G-16 (enriched—62% (S)-enantiomer/38% (R) enantiomer) (11.1 g,41.5 mmol) was dissolved in 120 mL EtOAc and treated with(S)-α-methylbenzylamine (6.52 g, 53.79 mmol). The resulting suspensionwas heated to reflux until all solids dissolved, at which time thesolution was allowed to cool to room temperature overnight. The reactionflask was cooled to 0° C. for 1 hour. The resulting solids were filteredoff and washed with cold Et₂O. HPLC analysis of isolated solid (as thefree acid): (AS chiralpak column, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1%Formic acid).

-   -   retention time: 15.86 min. (79.43%) 19.34 min. (20.57%)

The isolated solids were suspended in EtOAc (150 mL) and isopropanol (10mL) and heated to reflux on a steam bath until all solids dissolved. Thesolution was allowed to cool to room temperature overnight and thencooled to 0° C. for 1 hour. The resulting solids were filtered off andwashed with cold Et₂O to afford the title compound. HPLC analysis ofisolated solid (as the free acid): (AS chiralpak column, 0.8 mL/min.,98% Hexanes/2% IPA/+0.1% Formic acid).

-   -   retention time: 15.83 min. (92.0%) 19.34 min. (8.0%)

The isolated solids in EtOAc (130 mL) and isopropanol (6 mL) were againheated to reflux on a steam bath until the solids dissolved. The steamwas shut off, and the solution was allowed to cool to room temperatureovernight. The reaction flask was cooled to 0° C. for 1 hour. Theresulting solids were filtered off and washed with cold Et₂O to affordthe title compound. HPLC analysis of isolated solid (as the free acid):(AS chiralpak column, 0.8 mL/min., 98% Hexanes/2% IPA/+0.1% Formicacid).

-   -   retention time: 15.83 min. (96.7%) 19.34 min. (3.3%)

EXAMPLE H

Bis [3-methoxy-3-oxopropanoato-(1-)-O,O′]magnesate

Monomethyl malonate (2.39 g, 20 mmol) and magnesium ethoxide (1.16 g, 10mmol) in THF (50 mL) were stirred for 3 hours at room temperature. Thesolution was concentrated under vacuum to give the title compound. Theproduct was carried on crude to the next step.

General Method 11. Preparation of Chiral (or Racemic) β-Ketoester fromβ-Hydroxy Acid for the Alternate Synthesis of Intermediate4-Hydroxy-5,6-dihydro-pyran-ones

A solution of the chiral β-hydroxyacid as isolated above (or the racemicentity from Table H) (1.0 equiv.), THF (30 mL), and carbonyldiimidazole(1.2-3 equiv.) was stirred for 3 to 18 hours at room temperature. Bis[3-methoxy-3-oxopropanoato (1-)-O,O′] magnesate from Example H (1 to 2equiv.) was added, and the reaction was stirred for 6 to 72 hours atroom temperature. The reaction was concentrated and the residuepartitioned between EtOAc and 1N HCl. The organic layer was washed withaqueous NaHCO₃ and brine, dried (MgSO₄) and concentrated. Purificationwas accomplished by silica gel chromatography; alternatively, thematerial could be carried on crude.

EXAMPLE I-1 (S)

(S)-5-Hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic acidethyl ester

The title compound was prepared as described in General Method 11 using(S)-3-hydroxy-4-methyl-3-(2-thiophen-3-yl-ethyl)-pentanoic acid (fromExample G-1 (S); 7.81 mmol), carbonyl diimidazole (8.59 mmol), bis[3-methoxy-3-oxopropanoato(1-)-O,O′]magnesate (15.62 mmol) and THF (85mL). Purification was accomplished using silica gel chromatography,eluting with 100% CH₂Cl₂.

¹H NMR (CDCl₃): δ 0.94 (dd, 6H), 1.27 (t, 3H), 1.75-190 (m, 2H), 1.9-2.0(m, 1H), 2.65-2.75 (m, 3H), 2.80 (d, 1H), 3.48 (s, 2H), 4.15-4.25 (m,2H), 6.93 (m, 2H), 7.2-7.3 (m, 1H).

EXAMPLE I-2 (S)

5-[2-(3-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic acidethyl ester, (S) enantiomer

The title compound was prepared following General Method 11 fromcompound G-2 (S) (5.85 g, 23.00 mmol) and CDI (8.21 g, 50.61 mmol) in100 mL of THF. After 3.5 hours stirring under N₂ at room temperature,bis [3-methoxy-3-oxopropanoato(1-)-O,O′]magnesate (13.94 g, 48.31 mmol)was added, and the mixture was stirred at room temperature overnight.The product was purified via silica gel chromatography, eluting with 4:1hexanes:EtOAc to afford the title compound.

¹H NMR (CDCl₃): δ 0.93 (d, 3H), 0.95 (d, 3H), 1.27 (m, 3H), 1.77-1.83(m, 2H), 1.91-2.01 (m, 1H), 2.63-2.69 (m, 2H), 2.71 (d, 1H), 2.83 (d,1H), 3.48 (s, 2H), 3.61 (s, 1H), 4.19 (m, 2H), 6.84-6.90 (m, 2H), 6.95(d, 1H), 7.19-7.24 (m, 1H).

The following β-ketoesters were prepared in similar fashion from theappropriate chiral (or racemic—Examples G-1 to G-16) β-ketoacids:

TABLE I Preparation of β-Ketoesters

Analytical Data Example R₁₄ Chirality (¹H NMR or MS) I-1 (R)

R (CDCl₃): δ 0.94(dd, 6H), 1.27(t, 3H), 1.75-1.90(m, 2H), 1.9-2.0(m,1H), 2.65-2.75(m, 3H), 2.80(d, 1H), 3.48(s, 2H), 4.15-4.25(m, 2H),6.93(m, 2H), 7.2-7.3(m, 1H). I-2 (R)

R I-3 (R)

R (CDCl₃): δ 0.93(d, 3H), 0.95(d, 3H), 1.27(m, 3H), 1.77(m, 2H),1.90-2.00(m, 1H), 2.62(m, 2H), 2.70(d, 1H), 2.83(d, 1H), 3.48(d, 2H),3.61(s, 1H), 4.19(m, 2H), 6.85-6.90(m, 1H), 6.94-7.09(m, 2H). I-3 (S)

S I-4

± MS(APCI): 373(M − H) I-5

± MS(APCI): 373(M − H) I-6

± MS(APCI): 373(M − H) I-7

± MS(APCI): 391(M − H) I-8

± MS(APCI): 391(M − H) I-9 (S)

S I-10 (S) Ph S (CDCl₃): δ 0.93(d, 3H), 0.96(d, 3H), 1.26(t, 3H),1.79-1.85(m, 2H), 1.93-2.02(m, 1H), 2.64-2.69(m, 2H), 2.72(d, 1H),2.83(d, 1H), 3.48(d, 2H), 4.18(q, 2H), 7.15-7.20(m, 3H), 7.26-7.31(m,2H). I-10 (R) Ph R (CDCl₃): δ 0.93(d, 3H), 0.96(d, 3H), 1.26(t, 3H),1.79-1.85(m, 2H), 1.93-2.02(m, 1H), 2.64-2.69(m, 2H), 2.72(d, 1H),2.83(d, 1H), 3.47(s, 2H), 4.19(q, 2H), 7.15-7.20(m, 3H), 7.25-7.31(m,2H). I-11 (R)

R (CDCl₃): δ 0.93(d, 3H), 0.95(d, 3H), 1.26(t, 3H), 1.75-1.81(m, 2H),1.91-2.01(m, 1H), 2.64-2.69(m, 2H), 2.71(d, 1H), 2.83(d, 1H), 3.48(s,2H), 4.18(q, 2H), 6.92-6.98(m, 2H), 7.10-7.15(m, 2H). I-11 (S)

S (CDCl₃): δ 0.93(d, 3H), 0.95(d, 3H), 1.26(t, 3H), 1.75-1.81(m, 2H),1.91-2.00(m, 1H), 2.60-2.68(m, 2H), 2.71(d, 1H), 2.83(d, 1H), 3.48(s,2H), 4.18(q, 2H), 6.92-6.98(m, 2H), 7.10-7.15(m, 2H). I-12

± I-13 (S)

S MS(APCI): 325(M − H) I-14 (S)

S (CDCl₃) δ 0.94(d, 3H), 0.96(d, 3H), 1.25(q, 3H), 1.69-1.76(m, 2H),1.95-2.04(m, 1H), 2.12(d, 3H), 2.64-2.70(m, 2H), 2.72(d, 1H), 3.48(s,2H), 3.61(s, 1H), 4.14- 4.24(m, 2H), 6.82-6.92(m, 2H), 7.02-7.10(m, 1H).I-15 (S)

S I-16 (S)

S

The compounds of Table I above are named.

-   -   I-2:        (R)-5-[2-(3-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester;    -   I-3:        5-[2-(3,4-Difluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester (R and S isomers);    -   I-4:        5-Hydroxy-6-methyl-3-oxo-5-[2-(2-trifluoromethyl-phenyl)-ethyl]-heptanoic        acid ethyl ester;    -   I-5:        5-Hydroxy-6-methyl-3-oxo-5-[2-(3-trifluoromethyl-phenyl)-ethyl]-heptanoic        acid ethyl ester;    -   I-6:        5-Hydroxy-6-methyl-3-oxo-5-[2-(4-trifluoromethyl-phenyl)-ethyl]-heptanoic        acid ethyl ester;    -   I-7:        5-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester;    -   I-8:        5-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester;    -   I-9:        (S)-5-Hydroxy-5-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-methyl-3-oxo-heptanoic        acid ethyl ester;    -   I-10: 5-Hydroxy-6-methyl-3-oxo-5-(2-phenyl-ethyl)-heptanoic acid        ethyl ester (R and S isomers);    -   I-11:        5-[2-(4-Fluoro-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester (S and R isomers);    -   I-12:        5-{2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-ethyl}-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester;    -   I-13:        (S)-5-Hydroxy-6-methyl-5-[2-(2-methyl-thiophen-3-yl)-ethyl]-3-oxo-heptanoic        acid ethyl ester;    -   I-14:        (S)-5-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester;    -   I-15:        (S)-5-[2-(3,5-Difluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester; and    -   I-16:        (S)-5-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-5-hydroxy-6-methyl-3-oxo-heptanoic        acid ethyl ester.        Alternate Synthesis of the Intermediate        4-Hydroxy-5,6-dihydro-pyran-2-ones (for Both Chiral and Racemic        Intermediates)

EXAMPLE J-1 (S)

(S)-4-Hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 8 using(S)-hydroxy-6-methyl-3-oxo-5-(2-thiophen-3-yl-ethyl)-heptanoic acidethyl ester (6.4 mmol), 0.1N NaOH (400 mL), and THF (40 mL). The productwas triturated from Et₂O, mp 117-123° C.

The following chiral dihydropyrones were prepared in a similar fashion:

TABLE J Synthesis of Chiral Dihydropyrones

Analytical Data Example R₁₅ Chirality (¹H NMR or MS) J-1 (R)

R mp 117-123° C. J-2 (S)

S (DMSO-d₆): δ 0.88(d, 3H), 0.90(d, 3H), 1.89-1.93(m, 2H), 2.08-2.15(m,1H), 2.32(d, 1H), 2.56-2.62(m, 3H), 4.96(s, 1H), 6.95-7.04(m, 3H),7.27-7.33(m, 1H), 11.37(bs, 1H). J-2 (R)

R (DMSO-d₆): δ 0.88(d, 3H), 0.90(d, 3H), 1.88-1.93(m, 2H), 2.05-2.15(m,1H), 2.33(d, 1H), 2.56-2.62(m, 3H), 4.96(s, 1H), 6.96-7.04(m, 3H),7.26-7.33(m, 1H), 11.36(bs, 1H). J-3 (S)

S (DMSO-d₆): δ 0.87(d, 3H), 0.90(d, 3H), 1.86-1.91(m, 2H), 2.04-2.13(m,1H), 2.33(d, 1H), 2.55-2.61(m, 3H), 4.95(s, 1H), 6.99-7.03(m, 1H),7.24-7.34(m, 2H). J-3 (R)

R (DMSO-d₆): δ 0.87(d, 3H), 0.90 (d, 3H), 1.86-1.91(m, 2H), 2.04-2.13(m,1H), 2.33(d, 1H), 2.55-2.61(m, 3H), 4.95(s, 1H), 6.99-7.03(m, 1H),7.24-7.34(m, 2H). J-4

± MS(APCI): 329(M + H) J-5

± MS(APCI): 329(M + H) J-6

± MS(APCI): 329(M + H) J-7

± MS(APCI): 347(M + H) J-8

± MS(APCI): 347(M + H) J-9

S (CDCl₃): δ 1.05(d, 3H), 1.06(d, 3H), 1.8(br.s, 1H), 1.9(m, 1H),2.03(m, 1H), 2.23(m, 1H), 2.66(d, 1H), 2.78(d, 1H), 2.81(m, 2H), 3.4(d,1H), 3.53(d, 1H), 4.63(d, 1H), 4.72(d, 1H), 7.24(m, 4H), J-10

S FROM 08/883,743 J-11 (S) Ph S (DMSO-d₆): δ 0.89(d, 3H), 0.91(d, 3H),1.81-1.98(m, 2H), 2.07-2.16(m, 1H), 2.31(d of ABX q, 1H), 2.54-2.63(m,3H), 4.96(s, 1H), 7.13-7.18(m, 3H), 7.23-7.28(m, 2H), 11.36(bs, 1H).J-11 (R) Ph R (DMSO-d₆) 0.89(d, 3H), 0.91 (d, 3H), 1.81-1.98(m, 2H),2.07-2.16(m, 1H), 2.31(d of ABX q, 1H), 2.55-2.63(m, 3H), 4.97(s, 1H),7.13-7.17(m, 3H), 7.23-7.28(m, 2H), 11.35(bs, 1H). J-12 (R)

R (DMSO-d₆) 0.87(d, 3H), 0.89(d, 3H), 1.81-1.93(m, 2H), 2.05-2.14(m,1H), 2.31(d of ABX q, 1H), 2.54-2.62(m, 3H), 4.95(s, 1H), 7.03-7.10(m,2H), 7.17-7.22(m, 2H). J-12 (S)

S (DMSO-d₆): δ 0.88 (d, 3H), 0.90(d, 3H), 1.82-1.92(m, 2H), 2.05-2.14(m,1H), 2.32(d of ABX q, 1H), 2.54-2.62(m, 3H), 4.96(s, 1H), 7.04-7.10(m,2H), 7.17-7.22(m, 2H). J-13

± MS(APCI): 295(M − H) J-14 (S)

S MS(APCI): 279(M − H) J-15 (S)

S (DMSO-d₆): δ 0.89(d, 3H), 0.91(d, 3H), 1.75-1.87(m, 2H), 2.10-2.19(m +d, 4H), 2.69 (d, 1H), 2.58-2.65(m, 3H), 4.96(s, 1H), 6.92-6.98(m, 2H),7.08-7.15(m, 1H) J-16 (S)

S (DMSO-d₆) δ 0.87(d, 3H), 0.89(d, 3H), 1.87-1.93(m, 2H), 2.04-2.13(m,1H), 2.34(d, 1H), 2.54-2.65(m, 3H), 4.95 (s, 1H), 6.91-7.04(m, 3H). J-17(S)

S (DMSO-d₆) δ 0.89(d, 3H), 0.91(d, 3H), 1.73-1.85(m, 2H), 2.-08-2.17(m,1H), 2.20(s, 3H), 2.28(d, 1H), 2.49-2.65 (m, partially obscured by DMSO,3H), 4.95(s, 1H), 6.86-6.98(m, 2H), 7.07-7.12 (m, 1H).

The compounds of Table J above are named:

-   -   J-2:        6-[2-(3-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one        (R and S isomers);    -   J-3:        6-[2-(3,4-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one        (R and S isomers);    -   J-4:        4-Hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;    -   J-5:        4-Hydroxy-6-isopropyl-6-[2-(3-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;    -   J-6:        4-Hydroxy-6-isopropyl-6-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;    -   J-7:        6-[2-(3-Fluoro-5-trifluoromethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   J-8:        6-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   J-9:        (S)-4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   J-11:        4-Hydroxy-6-isopropyl-6-(2-phenyl-ethyl)-5,6-dihydro-pyran-2-one        (R and S isomers);    -   J-12:        6-[2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one        (R and S isomers);    -   J-13:        4-Hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   J-14:        (S)-4-Hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   J-15:        (S)-6-[2-(3-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   J-16:        (S)-6-[2-(3,5-Difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;        and    -   J-17:        (S)-6-[2-(4-Fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one.        Synthesis of Tosylthiolate Side Chains        General Method 12. Preparation of Nitro Intermediates

The appropriate alkylbenzene (1 equiv.) was dissolved in acetic acid andacetic anhydride. To the solution was added sulfuric acid, followed by70% nitric acid or fuming nitric acid (1 to 1.5 equiv.; ratio ofconcentrated sulfuric acid to nitric acid is 1:2), dropwise at 0° C.After the addition, the reaction was warmed to room temperature. Thereaction mixture was kept at room temperature to 80° C. for 6 to 18hours. The reaction mixture was poured into ice and extracted withEtOAc. The crude product was purified by either distillation or by flashsilica gel chromatography.

EXAMPLE K

1-Bromo-4-tert-butyl-2-nitro-benzene

The reaction was done as described in General Method 12 using1-bromo-4-tert-butyl-benzene (15 g), acetic acid (10 mL), nitric acid(6.5 g), and sulfuric acid (13 g). MS(APCI): 291.

General Method 13. Preparation of Benzthiazoles

To the aryl amine (1 equiv.) in MeOH or acetic acid was added sodium orpotassium or ammonium thiocyanate (3-6 equiv.). The reaction was stirredat 0° C. to room temperature. This reaction mixture was cooled to 0° C.and treated dropwise with bromine (2-2.2 equiv.) or a solution of sodiumbromide (2-2.2 equiv.) and bromine (2-2.2 equiv.). After the additionwas complete, the reaction mixture was slowly warmed to room temperatureand stirred at room temperature for 4 to 24 hours. The reaction mixturewas added to sodium bicarbonate solution and extracted with EtOAc (2-4times). The EtOAc layer was separated, washed with H₂O and brine, anddried (MgSO₄). The organic layer was concentrated, and the residue waspurified either by crystallization or by flash silica gelchromatography.

EXAMPLE L-1

5-tert-Butyl-6-thiocyanato-benzothiazol-2-yl-amine

1-Bromo-4-tert-butyl-2-nitro-benzene (18 g) was reduced as described inGeneral Method 3 using 10% palladium on charcoal (1 g) and MeOH (100 mL)in a hydrogen atmosphere (50 psi). The catalyst was filtered, and thesolvents were evaporated. The residue was taken in EtOAc (100 mL) andwashed with saturated sodium bicarbonate solution and H₂O. The solutionwas dried and concentrated. The residue was purified by flashchromatography to give 3-tert-butyl-phenylamine. MS (APCI): 150 (M+H).

The title compound was prepared according to General Method 13 using3-tert-butyl-phenylamine (9.4 g, 63 mmol), sodium thiocyanate (30.7 g,379 mmol), sodium bromide (14.3 g, 139 mmol), bromine (22.2 g, 139 mmol)and MeOH (300 mL). The crude reaction mixture was purified by flashchromatography (20% EtOAc in hexanes to 75% EtOAc in hexanes aseluents). MS (APCI): 264 (M+H).

EXAMPLE L-2

5-iso-Propyl-6-thiocyanato-benzothiazol-2-yl-amine

The title compound was prepared according to General Method 13 using3-isopropyl-phenylamine (20.8 g, 154 mmol), sodium thiocyanate (74.8 g,923 mmol), sodium bromide (34.8 g, 338 mmol), bromine (54.1 g, 338mmol), and MeOH (300 mL). The crude reaction mixture was purified byflash chromatography (CH₂Cl₂ to 25% EtOAc in CH₂Cl₂ as eluents). MS(APCI): 250 (M+H).

EXAMPLES L-3, L-4, and L-5

2-Isopropyl-4-isothiocyanato-5-methyl-phenylamine,7-Isopropyl-4-methyl-6-thiocyanato-benzothiazol-2-yl-amine, and4-Isopropyl-7-methyl-6-thiocyanato-benzothiazol-2-yl-amine

The title compounds were prepared according to General Method 13 using2-isopropyl-5-methyl-phenylamine (contains approximately 10% of3-isopropyl-6-methyl-phenylamine) (20.0 g, 134 mmol), sodium thiocyanate(65.3 g, 805 mmol), sodium bromide (30.4 g, 295 mmol), bromine (47.2 g,295 mmol), and MeOH (300 mL). The crude reaction mixture was purified byflash chromatography (20% EtOAc in hexanes to 75% EtOAc in hexanes aseluents), which yielded three products:

-   -   L-3: 2-Isopropyl-4-isothiocyanato-5-methyl-phenylamine:        uppermost spot on tlc: MS (APCI): 207 (M+H).    -   L-4-4-Isopropyl-7-methyl-6-thiocyanato-benzothiazol-2-yl-amine:        middle sport on tlc: MS (APCI): 264 (M+H), 239.    -   L-5: 7-Isopropyl-4-methyl-6-thiocyanato-benzothiazol-2-yl-amine:        lowest spot on tlc: MS (APCI): 264 (M+H)

EXAMPLE L-6

6-tert-Butyl-4-thiocyanato-benzothiazol-2-yl-amine

The title compound was prepared according to General Method 13 using4-tert-butyl-phenylamine (16.2 g, 109 mmol), sodium thiocyanate (53.0 g,653 mmol), sodium bromide (24.6 g, 240 mmol), bromine (38.3 g, 240mmol), and MeOH (300 mL). The crude product was purified by silica gelchromatography (10-50% EtOAc in hexanes as eluents). MS (APCI): 263 (M).

General Method 14. Cleavage of SCN Group

A solution of the SCN intermediate in denatured EtOH was treated withdithiothreitol (3-5 equiv.) and 0.2 M KH₂PO₄ (in a ratio of 4:1EtOH:buffer). The mixture was stirred for 6 to 48 hours at 0° C. to 50°C. The solvent was evaporated, and H₂O and CHCl₃ were added; the organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The resulting residue was flash chromatographed on silica gel.

General Method 14b. Alternate Cleavage of the SCN Group

The thiocyante (1 eq.) was dissolved in THF and treated with sodiumhydrogen sulfide (3 eq.) and sodium borohydride (6 eq.). A mixture ofMeOH and water (2:1) was added dropwise at 0° C., and the reactionmixture was stirred at room temperature overnight. Water and toluenewere added, and the reaction was quenched with glacial acetic acid at 0°C. The organic layer was separated, washed with H₂O, and dried (MgSO₄.)The organic layer was concentrated, and the crude was used without anypurification.

EXAMPLE M-1

2-Amino-5-tert-butyl-benzothiazole-6-thiol

The title compound was prepared according to General Method 14 using5-tert-butyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-1; 8 g, 30mmol), dithiothreitol (18.7 g, 121 mmol), EtOH (200 mL), and phosphatebuffer (50 mL). MS (APCI): 239 (M+H).

EXAMPLE M-2

2-Amino-5-isopropyl-benzothiazole-6-thiol and5-Isopropyl-benzothiazole-6-thiol

The title compound was prepared according to General Method 14 using5-isopropyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-2; 23.5 g,94.4 mmol), dithiothreitol (58.2 g, 377 mmol), EtOH (300 mL), andphosphate buffer (150 mL). The reaction mixture was kept under refluxovernight. The reaction mixture contained a mixture of2-amino-5-isopropyl-benzothiazole-6-thiol and5-isopropyl-benzothiazole-6-thiol in 1:2 ratio. The crude reactionmixture was used as such without any further purification.2-Amino-5-isopropyl-benzothiazole-6-thiol: MS (APCI): 225 (M+H);5-Isopropyl-benzothiazole-6-thiol: MS (APCI): 210 (M+H).

EXAMPLE M-3

2-Amino-7-isopropyl-4-methyl-benzothiazole-6-thiol

The title compound was prepared according to General Method 14 using7-isopropyl-4-methyl-6-thiocyanato-benzothiazol-2-yl-amine (Example L-5;11.5 g, 43.7 mmol), dithiothreitol (27.0 g, 175 mmol), EtOH (200 mL),and phosphate buffer (50 mL). MS (APCI): 239 (M+H).

EXAMPLE M-4

2-Amino-6-tert-butyl-benzothiazole-4-thiol

The title compound was prepared according to General Method 14 using6-tert-butyl-4-thiocyanato-benzothiazol-2-yl-amine (Example L-6; 2.0 g.7.6 mmol), dithiothreitol (4.6 g, 30 mmol), phosphate buffer of pH 7 (10mL), and EtOH (50 mL). The crude product was used further without anypurification. MS (APCI): 239 (M+H).

EXAMPLE N

2-(Methyloxycarbonyl)amino-4-isopropyl-7-methyl-benzothiazole-6-thiol

To 4-isopropyl-7-methyl-6-thiocyanato-benzothiazol-2-yl-amine (ExampleL-4; 4.0 g, 17 mmol) dissolved in CH₂Cl₂ (25 mL) and pyridine (5 mL),was added methyl chloroformate at 0° C. The reaction mixture was stirredat room temperature for 2 hours. H₂O was added to the reaction mixturefollowed by EtOAc (100 mL). The organic layer was washed with 2N HCl,H₂O, saturated sodium bicarbonate solution and brine, and was dried(MgSO₄). The solvents were evaporated, and the residue was purified byflash chromatography (100% hexanes to 25% EtOAc in hexanes) to give2-(methyloxycarbonyl)amino-4-isopropyl-7-methyl-6-thiocyanato-benzothiazole.MS (APCI): 322 (M+H).

The title compound was prepared according to General Method 14 using2-(methyloxycarbonyl)amino-4-isopropyl-7-methyl-6-thiocyanato-benzothiazole(1.5 g, 4.7 mmol), dithiothreitol (2.9 g, 18.7 mmol), EtOH (50 mL), andphosphate buffer (15 mL). MS (APCI): 296 (M−H).

Preparation of Benzothiphenes

EXAMPLE O

3-tert-Butyl-2-mercapto-benzo[b]thiophene

A solution of 3-tert-butylbenzo[b]thiophene (2.00 g, 10.4 mmol; J. Chem.Soc., Perkin Trans. 1, 1972;3:414-18) in Et₂O (30 mL, N₂ atmosphere) wastreated with a 1.6 M hexane solution of nBuLi (3.75 mL, 12 mmol) andallowed to stir overnight. The mixture was then cooled to 0° C. andtreated with dry precipitated sulfur (0.38 g, 12 mmol). The mixture wasallowed to stir for 2 hours, then quenched with ice H₂O. The mixture waswashed with Et₂O, and the aqueous layer was acidified with 1 N HCl andextracted with Et₂O. The organic layers were combined, dried (MgSO₄),and concentrated. The crude thiol was used without purification in thenext step.

EXAMPLE P

2-(3,5-Dibromo-thiophen-2-yl)-propan-2-ol

A solution of 2,3,5-tribromothiophene (8.17 g, 25 mmol) in Et₂O (N₂atmosphere) was cooled to −78° C. and treated with a 1.6 M hexanesolution of nBuLi (15.6 mL, 25 mmol). The mixture was then stirred for10 minutes, then treated with acetone (1.84 mL, 25 mmol). The mixturewas then stirred for 30 minutes and quenched with H₂O. The mixture wasextracted with Et₂O; the organic layers were combined, dried (MgSO₄),and the solvent removed in vacuo. The residue was filtered through aplug of silica gel (gradient elution from hexanes to EtOAc) to providethe title compound.

¹H NMR (CDCl₃): δ 1.70 (s, 6H), 2.40 (br s, 1H), 6.89 (s, 1H).

EXAMPLE Q

(4-Bromo-5-isopropyl-thiophen-2-yl)-methanol

A solution of 2-(3,5-dibromo-thiophen-2-yl)-propan-2-ol (Example P; 7.64g, 25 mmol) in CH₂Cl₂ (100 mL) was cooled to 0° C. and treated withtriethylsilane (6.80 mL, 30.56 mmol) followed by triflouroacetic acid(40 mL). The mixture was stirred for 15 minutes and then concentrated invacuo. The residue was taken up in hexanes and filtered through a plugof silica gel. The solvent was removed in vacuo, and the residue wasdiluted with Et₂O and cooled to −78° C. (N₂ atmosphere). The mixture wastreated with a 1.6 M hexane solution of nBuLi (15.6 mL, 25 mmol),stirred 10 minutes, and treated with a solution of 4-formylmorpholine(2.88 mL, 25 mmol) in Et₂O (25 mL). The mixture was allowed to slowlycome to room temperature overnight, then quenched with H₂O and extractedwith Et₂O. The organic layers were combined, dried (MgSO₄), andconcentrated.

The residue was then taken up in MeOH (250 mL) and treated with anexcess of sodium borohydride. After 30 minutes, the mixture was dilutedwith Et₂O, washed with H₂O, and dried (MgSO₄). The solvent wasevaporated and the residue purified via silica gel chromatography(hexanes to 10% EtOAc:hexanes) to provide the title compound.

¹H NMR (CDCl₃): δ 1.28 (d, 6H), 1.73 (bs, 1H), 3.31 (sept, 1H), 4.73 (d,2H), 6.82 (d, 1H).

EXAMPLE R

(4-Bromo-5-isopropyl-thiophen-2-yl-methoxy)-tert-butyl-dimethyl-silane

A solution of (4-bromo-5-isopropyl-thiophen-2-yl)-methanol (Example Q;3.4 g, 14 mmol) in CH₂Cl₂ (4.0 mL) was treated with NEt₃ (2.8 mL, 20mmol), p-dimethylaminopyridine (0.050 g), andt-butyldimethylsilylchloride (2.41 g, 16.0 mmol). The mixture wasstirred for 14 hours, then diluted with Et₉O and washed with H₂O. Theorganic layer was dried (MgSO₄) and the solvent evaporated to providethe crude product, which was used without further purification.

¹H NMR (CDCl₃): δ 0.0 (s, 6H), 0.82 (s, 9H), 1.17 (d, 6H), 3.20 (sept,1H), 4.66 (d, 2H), 6.60 (s, 1H).

EXAMPLE S

5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-isopropyl-3-mercapto-thiophene

A solution of(4-bromo-5-isopropyl-thiophen-2-ylmethoxy)-tert-butyl-dimethyl-silane(Example R; 4.7 g, 13.5 mmol) in Et₂O (100 mL, N₂ atmosphere) was cooledto −78° C. and treated with a 1.6 M hexane solution of nBuLi (8.42 mL,13.5 mmol). After 10 minutes, dry triturated sulfur (0.43 g, 13.5 mmol)was added, and the mixture was allowed to warm to room temperature.After 2 hours the mixture was diluted with Et₂O and washed with 0.5 MHCl. The organic layer was dried (MgSO₄) and concentrated to give thetitle compound, which was used crude in the next step.

EXAMPLE T

5-tert-Butyl-4-hydroxy-2-methylbenzaldehyde

Aluminum chloride (26.6 g, 200 mmol) was added to chlorobenzene (40 mL),and the mixture was cooled to −10° C. A solution of2-tert-butyl-5-methylphenol (16.4 g, 100 mmol) in triethyl orthoformate(32.5 g, 220 mmol) was added dropwise. When addition was complete, thereaction mixture was warmed to 0° C. to 5° C. and kept at thattemperature for 6 hours. Five percent HCl (100 mL) was added, and themixture was extracted with 1:1 EtOAC:toluene. The organic phase wasextracted with 23% KOH (3×50 mL) and water (25 mL), and the waterextract was combined with the KOH extracts. The pH of the combinedaqueous extracts was adjusted to 4 with 37% HCl. The resultingprecipitate was filtered, washed with water (3×50 mL), and dried to givethe title compound, mp 171-171° C.

EXAMPLE U

Dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl)ester

Ten percent KOH (80 mL) was added to a mixture of5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (Example T; 99.0 g, 515mmol) in water (180 mL) and THF (135 mL.) The mixture was treated with asolution of N,N-dimethylthiocarbamoyl chloride (86.1 g) in THF (108 mL)over a 2-hour period with simultaneous addition of 10% KOH in order tohold the pH of the reaction mixture between 12.0 and 12.3. Afterapproximately 70% of the dimethylthiocarbamoyl chloride-THF solution hadbeen added, vacuum was applied to the reaction mixture to remove theTHF; during this distillation, the simultaneous additions of 10% KOH andthe dimethylthiocarbamoyl chloride-THF solution were continued whilemaintaining the pH range between 12.0 and 11.6 and the reactiontemperature between 23° C. to 25° C. The distillation was continued for10 minutes after all the dimethylthiocarbamoyl chloride solution hadbeen added. Stirring at ambient pressure and temperature was continuedfor another 90 minutes, during which time the pH was stable between 11.6and 11.75. A solution of EtOAc (150 mL) and heptane (150 mL) was addedto the reaction mixture, and after stirring and settling, the layerswere separated and the aqueous layer extracted with 1:1 heptane:EtOAc.The combined organic extracts were extracted with 10% KOH (2×100 mL) andwater (2×90 mL) and concentrated. The residue was diluted with MeOH (120mL). The solution was warmed to 45° C. and H₂O (20 mL) was added. Thesolution was cooled to room temperature, 50% NaOH (170 mg) was added,and the solution was concentrated. This residue was redissolved in MeOH(120 mL) at 50° C. and H₂O (15 mL) was added. The solution was cooledslowly to −5° C. with the addition of dimethylthiocarbamic acidO-(2-tert-butyl-4-formyl-5-methyl-phenyl)ester seed crystals to promotecrystallization. The mixture was filtered and the solid washed with 4:1MeOH:H₂O to give the title compound, mp 80-81° C.

EXAMPLE V

(5-tert-Butyl-4-mercapto-5-methyl-phenyl)methanol

Dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl)ester(Example U; 24.0 g, 85.9 mmol) was treated with tetraethylene glycoldimethyl ether (65 g), and the mixture was stirred and heated underargon to 275° C. The solution was heated at this temperature for 30minutes. The solution was cooled, and H₂O was added. The mixture wascooled to 0° C. and filtered; the solid was washed with H₂O to givedimethyl thiocarbamic acidS-(2-tert-butyl-4-formyl-5-methyl-phenyl)ester.

The crude solid was treated with MeOH (40 mL) and THF (30 mL) followedby slow addition (20 minutes) of NaBH₄ (14.1 g of a 12 weight percentsolution in 14 M NaOH), while maintaining the temperature below 8° C.The resulting solution was stirred at 20° C. to 25° C. for 90 minutes.Fifty percent NaOH (4 g) was added, and the solution was heated toreflux for 3 hours. The mixture was cooled to room temperature, treatedwith H₂O (110 mL) and toluene (70 mL), and acidified to pH 4 with 37%HCl. The aqueous layer was separated and extracted with toluene (2×15mL). Concentration gave the title compound which was used withoutfurther purification in the next step.

EXAMPLE W

3-tert-Butyl-4-dimethylcarbamoylsulfanyl-benzoic acid methyl ester

A solution of 3.0 g (14.4 mmol) of 3-tert-butyl-4-hydroxy-benzoic acidmethyl ester (Aust. J. Chem., 1978;31:907-916), cesium carbonate (7.04g, 21.6 mmol), and acetonitrile (50 mL) was heated to reflux and thentreated with N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) allat once. The mixture was refluxed for 2 hours, cooled to roomtemperature, and quenched with 1N HCl. The solution was extracted withEtOAc; the organic layer was washed with 1N NaOH and brine, dried(MgSO₄), and concentrated. The residue was chromatographed over silicagel, eluting with 3:2 hexane:EtOAc, to give3-tert-butyl-4-dimethylthiocarbamoyloxy-benzoic acid methyl ester.

¹H NMR (CDCl₃): δ 1.39 (s, 9H), 3.44 (d, 6H), 3.90 (s, 3H), 7.09 (d,1H), 7.89 (dd, 1H), 8.12 (m, 1H).

Neat 3-tert-butyl-4-dimethylthiocarbamoyloxy-benzoic acid methyl ester(2.71 g, 9.2 mmol) was heated to 230° C. for 2 hours and then cooled toroom temperature. The material was chromatographed over silica gel,eluting with 7:3 hexane:EtOAc, to give the title compound.

¹H NMR (CDCl₃): δ 1.50 (s, 9H), 3.11 (br s, 6H), 3.91 (s, 3H), 7.53 (d,1H), 7.84 (dd, 1H), 8.13 (d, 1H).

EXAMPLE X

(3-tert-Butyl-4-mercapto-phenyl)methanol

A solution of 2.1 g (7.1 mmol) of3-tert-butyl-4-dimethylcarbamoylsulfanyl-benzoic acid methyl ester(Example W) in toluene (100 mL) was cooled to −78° C. and treated with42 mL of DIBAL (1.0 M in CH₂Cl₂; 42 mmol). The reaction mixture wasallowed to warm to room temperature overnight. The reaction was quenchedcautiously with saturated aqueous citric acid and extracted with EtOAc(2×100 mL). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated. Chromatography of the residue over silicagel, eluting with 3:2 hexane:EtOAc, gave the title compound.

¹H NMR (CDCl₃): δ 1.48 (s, 9H), 1.97 (br s, 1H), 3.61 (s, 1H), 4.59 (s,2H), 7.02 (dd, 1H), 7.20 (d, 1H), 7.34 (d, 1H).

EXAMPLE Y

(5-tert-Butyl-4-hydroxy-2-methyl-phenyl)-acetic acid, methyl ester

A solution of 8.5 g (51 mmol) of (4-hydroxy-2-methyl-phenyl)-acetic acid(Indian J. Chem. Sect. B. 26, 1987:679-682), tert-butanol (60 g), andconc. sulfuric acid (2 mL) was stirred at 70° C. for 5 days. Thesolution was cooled to room temperature, poured into water, andextracted with EtOAc. The organic extract was washed with brine, dried(MgSO₄), and concentrated to give(5-tert-butyl-4-hydroxy-2-methyl-phenyl)-acetic acid.

¹H NMR (CDCl₃): δ 1.33 (s, 9H), 2.14 (s, 3H), 3.54 (s, 2H), 6.47 (s,1H), 7.00 (s, 1H).

A mixture of the (5-tert-butyl-4-hydroxy-2-methyl-phenyl)-acetic acidisolated above (11.3 g, 51 mmol), MeOH (150 mL), and conc. sulfuric acid(2 mL) was refluxed overnight. The solution was cooled to roomtemperature and concentrated. The residue was partitioned between EtOAcand water; the organic phase was washed with brine, dried (MgSO₄), andconcentrated. The product was chromatographed over silica gel, elutingwith hexane:EtOAc, to give the title compound.

¹H NMR (CDCl₃): δ 1.35 (s, 9H), 2.16 (s, 3H), 3.54 (s, 2H), 3.67 (s,3H), 6.46 (s, 1H), 7.01 (s, 1H).

EXAMPLE Z

(5-tert-Butyl-4-dimethylcarbamoylsulfanyl-2-methyl-phenyl)-acetic acidmethyl ester

A solution of 3.0 g (13 mmol) of(5-tert-butyl-4-hydroxy-2-methyl)-phenyl acetic acid, methyl ester(Example Y) in 20 mL of DMF was treated portionwise with 0.60 g (15mmol) of NaH and stirred at room temperature for 1 hour.N,N-dimethylthiocarbamoyl chloride (2.35 g, 19 mmol) was added all atonce, and the reaction mixture was stirred at 70° C. overnight. Waterwas added: the solution was extracted with EtOAc. The organic layer wasseparated, washed with brine, dried (MgSO₄), and concentrated. The crudematerial was chromatographed over silica gel, eluting with hexane:EtOAc3:1, to give(5-tert-butyl-4-dimethylthiocarbamoyloxy-2-methyl-phenyl)-acetic acidmethyl ester.

¹H NMR (CDCl₃): δ 1.30 (s, 9H), 2.22 (s, 3H), 3.40 (d, 6H), 3.58 (s,2H), 3.66 (s, 3H), 6.80 (s, 1H), 7.17 (s, 1H).

The product isolated above (2.1 g, 6.5 mmol) was heated neat to 310° C.for 1 hour and then cooled to room temperature. The residue waschromatographed on silica gel, eluting with hexane:EtOAc 2: 1, to givethe title compound.

¹H NMR (CDCl₃): δ 1.41 (s, 9H), 2.22 (s, 3H), 3.00-3.10 (br d, 6H), 3.58(s, 2H), 3.65 (s, 3H), 7.22-7.24 (m, 2H).

EXAMPLE AA

2-(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-ethanol

A solution of 0.68 g (2.1 mmol) of(5-tert-butyl-4-dimethylcarbamoylsulfanyl-2-methyl-phenyl)-acetic acidmethyl ester (Example Z) in 20 mL of toluene was cooled to −78° C. andtreated dropwise with 1.0 M DIBAL in CH₂Cl₂ (10 mL; 10 mmol). The coldbath was removed, and the mixture was stirred at room temperature for 2hours. Saturated citric acid was added cautiously. H₂O and EtOAc wereadded, and the mixture was filtered. The filtrate was transferred to aseparatory funnel where the aqueous phase was isolated and re-extractedwith EtOAc. The organic extracts were combined, washed with brine, anddried (MgSO₄). Concentration gave an oil which was chromatographed oversilica gel, eluting with 1:1 hexane:EtOAc, to give the title compound.

¹H NMR (CDCl₃): δ 1.42 (s, 9H), 2.20 (s, 3H), 2.79 (t, 2H), 3.49 (t,1H), 3.76 (t, 2H), 7.01 (s, 1H), 7.11 (s, 1H).

General Method 15. Preparation of Tosyl Reagents

A solution of p-toluenesulfonyl bromide (1 equiv.), a base such as NEt₃or pyridine (1-1.5 equiv.), and a solvent such as CCl₄ or EtOAc at 0° C.to 24° C. was treated with a solution of the appropriate thiol (1equiv.) in CCl₄ or EtOAc in a dropwise fashion. Addition was complete in0.5 to 11 hours. The reaction was allowed to warm to room temperature.H₂O was added; the organic layer was separated, washed with saturatedaqueous NH₄Cl and brine, and dried (MgSO₄). Concentration gave a residuewhich could be purified either by silica gel chromatography or bytrituration.

EXAMPLE BB-1

Toluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester

The title compound was prepared according to General Method 15 using2-amino-5-tert-butyl-benzothiazole-6-thiol (7.0 g, 29 mmol), pyridine(2.3 g, 29 mmol), tosyl bromide (6.9 g, 29 mmol), carbon tetrachloride(100 mL), and EtOAc (100 mL). The crude reaction mixture was purified byflash chromatography (5% EtOAc in hexanes to 50% EtOAc in hexanes aseluents). MS(APCI): 393 (M+H).

EXAMPLE BB-2

Toluene-4-thiosulfonic aidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester

A solution of (5-tert-butyl-4-mercapto-5-methyl-phenyl)methanol (fromExample V), pyridine (6.12 G), and toluene (30 mL) was slowly added(over 3 hours) at 40° C. to a prestirred solution of toluenesulfonylchloride (16.6 g) and lithium bromide (8.0 g) in THF (75 mL). Theresulting mixture was stirred at 40° C. for 2 hours and then overnightat room temperature. H₂O (70 mL) and EtOAc (30 mL) were added. Theorganic layer was separated and washed with 10% HCl (2×50 mL) and H₂O(50 mL). The solution was concentrated to give a residue which waswarmed to 60° C. and treated with heptane. This solution was stirred andcooled to 10° C.; the solids were filtered and washed with 1:1toluene:heptane. Upon drying in vacuo, the title compound was obtained,mp 121-122° C.

The following tosylthiolates were prepared using the appropriate thioland following General Method 15:

TABLE K Thiotosylate Side Chains Prep. of Starting Materials ExampleStructure ¹H NMR or MS Data Examples L-2 and M-2 BB-3

MS(APCI): 378 Examples L-2 and M-2 BB-4

MS(APCI): 364(M + H) Examples L-5 and M-3 BB-5

MS(APCI): 393(M + H) Examples L-4 and N BB-6

MS(APCI): 451(M + H) Examples L-6 and M-4 BB-7

MS(APCI): 393(M + H) Example O BB-8

(CDCl₃): δ 1.54(s, 9H), 2.43(s, 3H), 7.24(d, 2H), 7.32-7.39(m, 2H),7.62(d, 2H), 7.69- 7.75(m, 1H), 8.17- 8.21(m, 1H). Example P-S BB-9

(CDCl₃): δ 0.00(s, 6H), 0.82(s, 9H), 0.91(d, 6H), 2.31(s, 3H),2.93(sept., 1H), 4.65(d, 2H), 6.60(s, 1H), 7.13(d, 2H), 7.41(d, 2H).BB-10

USSM 08/883,743 BB-11

USSN 08/883,743 BB-12

USSN 08/883,743 Examples W and X BB-13

(CDCl₃): δ 1.23(s, 9H), 2.40(s, 3H), 4.73(s, 2H), 7.23(m, 3H), 7.43(m,1H), 7.46-7.50(m, 2H), 7.61(d, 1H). Examples Y, Z and AA BB-14

(CDCl₃): δ 1.21(s, 9H), 2.17(s, 3H), 2.39(s, 3H), 2.85(t, 2H), 3.80(t,2H), 7.18-7.22(m, 4H), 7.47(d, 2H). Example BB-11 BB-15

Examples CC-FF BB-16

(CDCl₃): δ 1.28(s, 9H), 1.69(s, 9H), 2.4(s, 3H), 6.5(d, 1H), 7.2 (d,2H), 7.44(d, 2H), 7.61(d, 1H), 7.81(s, 1H), 8.28(br s, 1H). ExamplesGG-LL BB-17

MS(APCI): 462 (M + H) Examples MM-NN BB-18

(CDCl₃): δ 1.22(s, 9H), 2.44(s, 3H), 2.99(t, 2H), 4.03(t, 2H), 7.22(d,2H), 7.39(d, 2H), 7.42(s, 1H), 7.66(s, 1H), 7.81(d, 2H), 7.94 (d, 2H).Examples OO-1-VV-1 BB-19

MS(APCI): 347 (M + H). Examples OO-2-VV-2 BB-20

MS(APCI): 361 (M + H). Examples OO-2-VV-2 BB-21

MS(APCI): 375 (M − H). Examples WW-AAA BB-22

MS(APCI): 432 (M + H) Examples BBB-DDD BB-23

MS(APCI): 405 (M + H) Example BB-1 BB-24

MS(APCI): 558 (M + H) Example BB-1 BB-25

MS(APCI): 471 (M + H) Example BB-1 BB-26

MS(APCI): 435 (M + H) Example VV-1 BB-27

MS(APCI): 363 (M + H)

The compounds from Table K above are named:

-   -   BB-3: Toluene-4-thiosulfonic acid        S-(2-amino-5-isopropyl-benzothiazol-6-yl)ester;    -   BB-4: Toluene-4-thiosulfonic acid        S-(5-isopropyl-benzothiazol-6-yl)ester;    -   BB-5: Toluene-4-thiosulfonic acid        S-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester;    -   BB-6: Toluene-4-thiosulfonic acid        S-(4-isopropyl-2-methoxycarbonylamino-7-methyl-benzothiazol-6-yl)ester;    -   BB-7: Toluene-4-thiosulfonic acid        S-(2-amino-6-tert-butyl-benzothiazol-4-yl)ester;    -   BB-8: Toluene-4-thiosulfonic acid        S-(3-tert-butyl-benzo[b]thiophen-2-yl)ester;    -   BB-9: Toluene-4-thiosulfonic acid        S-[5-(tert-butyl-silanyloxymethyl)-2-isopropyl-thiophen-3-yl]ester;    -   15 BB-13: Toluene-4-thiosulfonic acid        S-(2-tert-butyl-4-hydroxymethyl-phenyl)ester;    -   BB-14: Toluene-4-thiosulfonic acid        S-[2-tert-butyl-4-(2-hydroxy-ethyl)-5-methyl-phenyl]ester; and    -   BB-15: Benzenesulfonothioic acid, 4-methyl-,        S-[2-(1,1-dimethylethyl)-5-methyl-4-[[[[(5-trifluoromethyl)-2-pyridinyl]sulfonyl]amino]phenyl]ester;    -   BB-16:        6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-indole-1-carboxylic        acid tert-butyl ester;    -   BB-17:        6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-2,3-dihydro-indole-1-carboxylic        acid tert-butyl ester;    -   BB-18: Toluene-4-thiosulfonic acid        S-[6-tert-butyl-1-(4-cyanobenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]ester;    -   BB-19: Toluene-4-thiosulfonic acid        S-(6-isopropyl-3H-benzoimidazol-5-yl)ester;    -   BB-20: Toluene-4-thiosulfonic acid        S-(6-tert-butyl-3H-benzoimidzol-5-yl)ester;    -   BB-21: Toluene-4-thiosulfonic acid        S-(6-tert-butyl-2-oxo-2,3-dihydro-1H-benz-oimidzol-5-yl)ester;    -   BB-22:        6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-1H-indole-2-carboxylic        acid ethyl ester;    -   BB-23: Toluene-4-thiosulfonic acid        S-(7-tert-butyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)ester;    -   BB-24: Toluene-4-thiosulfonic acid        S-[5-tert-butyl-2-(4-cyanobenzenesulfonyl-amino)-benzothiazol-6-yl)]ester;    -   BB-25: Toluene-4-thiosulfonic acid        S-(6-tert-butyl-2-methanesulfonylamino-benzothiazol-6-yl)ester;    -   BB-26: Toluene-4-thiosulfonic acid        S-(2-acetylamino-5-tert-butyl-benzothiazol-6-yl)ester; and    -   BB-27: Toluene-4-thiosulfonic acid        S-(6-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)ester.

EXAMPLE BB-15

Benzenesulfonothioic acid, 4-methyl-,S-[2-(1,1-dimethylethyl)-5-methyl-4-[[[[(5-trifluoromethyl)-2-pyridinyl]sulfonyl]amino]phenyl]ester

Compound BB-11 (0.5 g, 1.43 mmol) was dissolved in pyridine (5 mL) andCH₂Cl₂ (2 mL). To this solution was added 0.53 g (2.16 mmol) of5-(trifluoromethyl)pyridine-2-sulfonyl chloride (J. Amer. Chem. Soc.,1997;119(15):3627-3628), and the reaction mixture was stirred under N₂at room temperature overnight. 1N HCl was then added; the mixture wasextracted with EtOAc, washed with 1 N HCl and brine, dried (MgSO₄),filtered, and concentrated. The resulting residue was chromatographedover silica gel, eluting with 9:1 CH₂Cl₂:EtOAc to afford the desiredproduct.

¹H NMR (CDCl₃): δ 1.13 (s, 9H), 2.19 (s, 3H), 2.42 (s, 3H), 6.83 (s,1H), 7.22 (d, 2H), 7.40 (s, 1H) 7.45 (d, 2H), 8.08 (d, 1H), 8.15 (m,1H), 8.99 (s, 1H).

EXAMPLE BB-24

Toluene-4-thiosulfonic acidS-[5-tert-butyl-2-(4-cyanobenzenesulfonyl-amino)-benzothiazol-6-yl)]ester

The title compound was prepared as described in Example BB-15 usingtoluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in ExampleBB-1; 1.0 g, 3.37 mmol), 4-cyanobenzenesulfonyl chloride (0.68 g, 3.37mmol), pyridine (10 mL) and CH₂Cl₂ (3 mL). The crude product waspurified by flash silica gel chromatography (20%-70% EtOAc in hexanes aseluents). MS(APCI): 558 (M+H).

EXAMPLE BB-25

Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-methanesulnoylamino-benzothiazol-6yl)ester

The title compound was prepared as described in Example BB-15 usingtoluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in ExampleBB-1; 1.75 g, 4.47 mmol), methanesulfonyl chloride (1.02 g, 8.94 mmol),pyridine (3 mL), DMAP (0.3 g) and CH₂Cl₂ (20 mL). The crude product waspurified by flash silica gel chromatography (20%-70% EtOAc in hexanes aseluents). MS(APCI): 471 (M+H).

EXAMPLE BB-26

Toluene-4-thiosulfonic acidS-(2-acetylamino-5-tert-butyl-benzothiazol-6-yl)ester

The title compound was prepared as described in Example BB-15 usingtoluene-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (prepared in ExampleBB-1; 1.75 g, 4.47 mmol), acetyl chloride (4 mL), pyridine (5 mL), DMAP(0.3 g) and CH₂Cl₂ (20 mL). The crude product was purified by flashsilica gel chromatography (20%-70% EtOAc in hexanes as eluents).MS(APCI): 435 (M+H).

EXAMPLE BB-27

Toluene-4-thiosulfonic acidS-(6-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)ester

Toluene-4-thiosulfonic acid S-(1,2-diamino-5-isopropyl-phenyl)ester(prepared in Example VV-1 below; 0.5 g, 1.5 mmol) and triphosgene (0.15g, 0.5 mmol) were dissolved in THF (30 mL). NEt₃ (1 mL) was added, andthe reaction mixture was stirred at 90° C. for 1.5 hours. The crudereaction mixture was subjected to flash silica gel chromatography (EtOActo 2%-10% MeOH in CH₂Cl₂ as eluents). MS(APCI): 363 (M+H).

EXAMPLE CC

(5-tert-Butyl-2-methyl-phenyl)-carbamic acid tert-butyl ester

5-tert-Butyl-2-methyl-phenylamine (50 g, 307 mmol) in 500 mL of hexaneswas treated with di-t-butyl dicarbonate (80.3 g, 368 mmol.). Thereaction mixture was kept under reflux overnight. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, washed withsaturated NaHCO₃ solution and brine, and dried (MgSO₄). Afterevaporation of the solvents, the crude reaction mixture was purified byflash silica gel chromatography to give the title compound. MS(APCI):262 (M−H).

EXAMPLE DD

(5-tert-Butyl-2-methyl-4-thiocyanto-phenyl)-carbamic acid tert-butylester

Thiocyanation was performed as described in the General Method 13 using(5-tert-butyl-2-methyl-phenyl)-carbamic acid tert-butyl ester (preparedin Example CC; 4.32 g, 15.82 mmol), sodium thiocyanate (7.7 g, 94.95mmol), sodium bromide (1.95 g, 18.98 mmol), bromine (3.03 g, 18.98mmol), and methanol (50 mL). MS(APCI): (M+H).

EXAMPLE EE

(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic acid tert-butyl ester

The title compound was prepared according to General Method 14 using(5-tert-butyl-2-methyl-4-thiocyanto-phenyl)-carbamic acid tert-butylester (prepared in Example DD; 30 g, 93.75 mmol), dithiothreitol (29 g,187.5 mmol) and phosphate buffer (50 mL). MS(APCI): 294 (M−H).

EXAMPLE FF

6-tert-Butyl-5-mercapto-indole-1-carboxylic acid tert-butyl ester

(5-tert-Butyl-4-mercapto-2-methyl-phenyl)-carbamic acid tert-butyl ester(prepared in Example EE; 20 g, 68 mmol) was dissolved in 100 mL of THF,cooled to −40° C., and treated dropwise with sec-butyllithium (1.3 M,156 mL, 203 mmol). After the addition was complete, the reaction mixturewas stirred at −30° C. to −45° C. for 30 minutes. To the mixture wasadded DMF (14.8 g, 203.39 mmol), and the solution was stirred at −35° C.for 30 minutes. The reaction mixture was slowly warmed to roomtemperature and was quenched with saturated NH₄Cl solution. EtOAc (200mL) was added; the organic layer was washed with brine, dried (MgSO₄)and concentrated. The residue was dissolved in 100 mL of THF and 2 mL ofconcentrated HCl and stirred at room temperature for 1 hour. Thesolution was diluted with EtOAc, washed with NaHCO₃ solution and brine,and dried (MgSO₄). The crude product was purified by flash silica gelchromatography to give the title compound. MS(APCI): 304 (M−H).

EXAMPLE BB-16

6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-indole-1-carboxylic acidtert-butyl ester

The title compound was prepared according to General Method 15 using6-tert-butyl-5-mercapto-indole-1-carboxylic acid tert-butyl ester(prepared in Example FF), pyridine, tosyl bromide, carbon tetrachloride,and EtOAc.

EXAMPLE GG

6-tert-Butyl-indole-1-carboxylic acid tert-butyl ester

(5-tert-Butyl-2-methyl-phenyl)-carbamic acid tert-butyl ester (preparedin Example CC; 19.7 g, 75 mmol) in 100 mL of THF was cooled to −40° C.To it was added tert-butyllithium (1.5 M, 100 mL, 150 mmol), dropwisewith stirring, at −45° C. to −35° C. After the addition was complete,the reaction was stirred at −35° C. for another 15 minutes. DMF (10.97g, 150 mmol) was added dropwise, and the reaction mixture was stirred at−35° C. for 30 minutes, followed by slow warming to room temperature.The reaction was quenched with saturated NH₄Cl solution and diluted withEtOAc. The organic layer was washed with brine, dried (MgSO₄), andconcentrated. The residue was dissolved in 100 mL of THF and 2 mL ofconcentrated HCl and stirred at room temperature for 1 hour. EtOAc wasadded, and the solution was washed with saturated NaHCO₃ solution andbrine and dried (MgSO₄). Concentration gave a residue that was purifiedby flash silica gel chromatography (5%-50% EtOAc in hexanes). MS(APCI):274 (M+H).

EXAMPLE HH

6-tert-Butyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

6-tert-Butyl indole-1-carboxylic acid tert-butyl ester (prepared inExample GG; 13.0 g, 48 mmol) was taken up in 500 mL of AcOH. 20% Pd/C (2g) was added, and the mixture was shaken under a hydrogen atmosphere of50 psi. The catalyst was filtered, and the filtrate was concentrated.The residue was dissolved in EtOAc, washed with saturated NaHCO₃solution and brine, and dried (MgSO₄). Concentration gave the titlecompound which was used without purification in the next step.

EXAMPLE II

6-tert-Butyl-2,3-dihydro-1H-indole

6-tert-Butyl-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester(Prepared in Example HH; 12.0 g) in CH₂Cl₂ (100 mL) was cooled to 0° C.and treated with HCl gas for 10 minutes. The reaction mixture was warmedto room temperature and stirred for 1 hour. The solvents wereevaporated; the residue was dissolved in EtOAc, washed with saturatedNaHCO₃ solution and brine, and dried (MgSO₄.) Concentration gave thetitle compound which was used without any further purification.MS(APCI): 176 (M+H).

EXAMPLE JJ

6-tert-Butyl-5-thiocyanato-2,3-dihydro-1H-indole

The title compound was prepared according to General Method 13 using6-tert-butyl-2,3-dihydro-1H-indole (prepared in Example II; 8.3 g, 47mmol), MeOH (100 mL), sodium thiocyante (23.1 g, 284.57 mmol), NaBr(5.86 g, 56.92 mmol) and bromine (9.1 g, 56.92 mmol). The crude reactionmixture was purified by flash silica gel chromatography (5%-75% EtOAc inhexanes). MS(APCI): 233 (M+H).

EXAMPLE KK

6-tert-Butyl-5-thiocyanato-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester

The title compound was prepared in the manner described in Example CCusing 6-tert-butyl-5-thiocyanato-2,3-dihydro-1H-indole (prepared inExample JJ; 2.0 g, 8.6 mmol), di-t-butyl dicarbonate (2.35 g, 10.8 mmol)and hexanes (150 mL). The crude product was purified by flash silica gelchromatography.

EXAMPLE LL

6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-carboxylic acid tert-butylester

The title compound was prepared according to General Method 14 using6-tert-butyl-5-thiocyanato-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester (prepared in Example KK; 2.0 g, 6.6 mmol),dithiothreitol (1.21 g, 7.9 mmol), EtOH (100 mL), and phosphate buffer(pH: 7.5, 10 mL). The crude product was used without any purification.

EXAMPLE BB-17

6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester

The title compound was prepared according to General Method 15 using6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-carboxylic acid tert-butylester (prepared in Example FF), pyridine, tosyl bromide, carbontetrachloride, and EtOAc.

EXAMPLE MM

4-(6-tert-Butyl-5-thiocyanato-2,3-dihydro-indole-1-sulfonyl)-benzonitrile

6-tert-Butyl-5-thiocyanato-2,3-dihydro-1H-indole (prepared in ExampleJJ; 4.5 g, 19 mmol) was taken in CH₂Cl₂ (50 mL) and treated with4-cyanophenylsulfonyl chloride (3.91 g, 19.4 mmol) and pyridine (5 mL).The reaction mixture was stirred overnight, quenched with saturatedNaHCO₃ solution, and diluted with EtOAc. The organic layer wasseparated, dried (MgSO₄), and concentrated. The crude product waspurified by flash chromatography (20%-75% EtOAc in hexanes as eluents).MS(APCI): 397 (M⁺).

EXAMPLE NN

4-(6-tert-Butyl-5-mercapto-2,3-dihydro-indole-1-sulfonyl)-benzonitrile

The title compound was prepared according to the General Method 14busing4-(6-tert-butyl-5-thiocyanato-2,3-dihydro-indole-1-sulfonyl)-benzonitrile(prepared in Example MM; 6.0 g, 15 mmol), sodium hydrogen sulfide (2.53g, 45.3 mmol), sodium borohydride (3.43 g, 90.7 mmol), MeOH (10 mL),water (5 mL), and AcOH (5 mL). The crude product was used furtherwithout any purification.

EXAMPLE OO-1

2,2,2-Trifluoro-N-(5-isopropyl-2-nitro-phenyl)-acetamide

Trifluoroacetic anhydride (50 mL) was cooled to 0° C. and treateddropwise with 3-isopropyl-phenylamine (5 g, 37.03 mmol). To theresulting solution was added potassium nitrate (4.12 g, 101.11 μmmol).After 1 hour, the reaction mixture was warmed to room temperature andstirred overnight. The reaction mixture was diluted carefully with icewater and extracted with EtOAc (4×100 mL). The organic layer was washedwith saturated NaHCO₃ solution and brine, dried (MgSO₄), andconcentrated. The crude product was used further without anypurification. MS(APCI): 275 (M−H).

EXAMPLE OO-2

N-(5-tert-Butyl-2-nitro-phenyl)-2,2,2-trifluoro-acetamide

The title compound was prepared following the procedure used in ExampleOO-1 using trifluoroacetic anhydride (300 mL), 3-tert-butyl-phenylamine(144 g, 951 mmol), and potassium nitrate (106 g, 1047 mmol). The crudeproduct was used further without any purification. MS(APCI): 289 (M−H).

EXAMPLE PP-1

5-Isopropyl-2-nitro-phenylamine

2,2,2-Trifluoro-N-(5-isopropyl-2-nitro-phenyl)-acetamide (prepared inExample OO-1; 9.4 g, 34 mmol) was dissolved in MeOH (30 mL) and treatedwith 7% aqueous potassium carbonate solution. The reaction mixture wasstirred overnight at room temperature. The reaction was diluted withwater (30 mL) and extracted with EtOAc (3×50 mL). The organic layer waswashed with saturated NaHCO₃ solution and brine, dried (MgSO₄), andconcentrated. The crude product was used further without anypurification. MS(APCI): 181 (M+H).

EXAMPLE PP-2

5-tert-Butyl-2-nitro-phenylamine

The title compound was prepared as outlined in Example PP-1 fromN-(5-tert-butyl-2-nitro-phenyl)-2,2,2-trifluoro-acetamide (prepared inExample OO-2; 248 g, 855 mmol), MeOH (500 mL), and 7% aqueous potassiumcarbonate solution. The crude product was used without any purification.MS(APCI): 195 (M+H).

EXAMPLE QQ-1

5-Isopropyl-2-nitro-4-thiocyanato-phenylamine

The title compound was prepared according to General Method 13 using5-isopropyl-2-nitro-phenylamine (prepared in Example PP-1; 5.4 g, 30mmol), sodium thiocyanate (14.6 g, 180 mmol), sodium bromide (3.7 g,35.99 mmol), bromine (5.75 g, 36.0 mmol), and MeOH (100 mL). The crudereaction mixture was purified by flash silica gel chromatography (5%-50%EtOAc in hexanes as eluents). MS(APCI): 238 (M+H).

EXAMPLE QQ-2

5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine

The title compound was prepared according to the General Method 13 using5-tert-butyl-2-nitro-phenylamine (prepared in Example PP-2; 170 g, 876mmol), ammonium thiocyanate (400 g, 5260 mmol), bromine (140 g, 876mmol), and MeOH (500 mL). The crude reaction mixture was purified byflash silica gel chromatography (5%-50% EtOAc in hexanes as eluents).MS(APCI): 252 (M+H).

EXAMPLE RR-1

4-Isopropyl-5-thiocyanato-benzene-1,2-diamine

5-Isopropyl-2-nitro-4-thiocyanato-phenylamine (prepared in Example QQ-1;7.83 g, 33 mmol) was hydrogenated using Raney nickel (2 g) and THF (100mL) in the presence of hydrogen (50 psi) as described in General Method3. MS(APCI): 208(M+H).

EXAMPLE RR-2

4-tert-Butyl-5-thiocyanato-benzene-1,2-diamine

5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine (prepared in ExampleQQ-2; 3 g, 12 mmol) was hydrogenated using Raney nickel (0.75 g) in thepresence of hydrogen as described in General Method 3. MS(APCI):222(M+H).

EXAMPLE SS-1

(2-tert-Butyoxycarbonylamino-4-isopropyl-5-thiocyanato-phenyl)-carbamicacid tert-butyl ester

Boc protection was performed as described in Example CC using4-isopropyl-5-thiocyanato-benzene-1,2-diamine (prepared in Example RR-1;4.49 g, 21.7 mmol), di-t-butyl dicarbonate (11.3 g, 52.0 mmol), hexanes(150 mL), and EtOAc (50 mL). The crude product was purified by flashsilica gel chromatography. MS(APCI): 406 (M−H).

EXAMPLE SS-2

(2-tert-Butoxycarbonylamino-4-tert-Butyl-5-thiocyanato-phenyl)-carbamicacid tert-butyl ester

Boc protection was performed as described in Example CC using4-tert-butyl-5-thiocyanato-benzene-1,2-diamine (prepared in ExampleRR-2; 9.78 g, 44.2 mmol), di-t-butyl dicarbonate (23.2 g, 106 mmol),hexanes (150 mL), and EtOAc (50 mL). The crude product was purified byflash silica gel chromatography. MS(APCI): 422 (M+H).

EXAMPLE TT-1

(2-tert-Butyoxycarbonylamino-4-isopropyl-5-mercapto-phenyl)-carbamicacid tert-butyl ester

The title compound was prepared according to General Method 14b using(2-tert-butyoxycarbonylamino-4-isopropyl-5-thiocyanato-phenyl)-carbamicacid tert-butyl ester (prepared in Example SS-1; 9 g, 22 mmol), sodiumhydrogen sulfide (3.7 g, 66 mmol), sodium borohydride (5.02 g, 132mmol), MeOH (20 mL), H₂O (5 mL), and AcOH (2 mL). The crude product wasused without any purification. MS(APCI): 381 (M−H).

EXAMPLE TT-2

(2-tert-Butoxycarbonylamino-4-tert-Butyl-5-mercapto-phenyl)-carbamicacid tert-butyl ester

The title compound was prepared according to General Method 14b using(2-tert-butoxycarbonylamino-4-tert-butyl-5-thiocyanato-phenyl)-carbamicacid tert-butyl ester (prepared in Example SS-2; 18 g, 43 mmol), sodiumhydrogen sulfide (7.2 g, 128 mmol), sodium borohydride (9.7 g, 256mmol), MeOH (150 mL), H₂O (50 mL), and AcOH (10 mL). The crude productwas used without purification.

EXAMPLE UU-1

Toluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-isopropyl-phenyl)ester

The title compound was prepared according to the General Method 15 using(2-tert-butyoxycarbonylamino-4-isopropyl-5-merccapto-phenyl)-carbamicacid tert-butyl ester (prepared in Example TT-1; 22.1 mmol), tosylbromide (5.2 g, 22 mmol), pyridine (5 mL), and EtOAc (50 mL). The crudeproduct was purified by flash chromatography (5%-60% EtOAc in hexanes aseluents). ¹H-NMR (CDCl₃): δ 0.97 (s, 6H), 1.53 (s, 18H), 2.4 (s, 3H),3.2 (m, 1H), 7.11 (br s, 1H), 7.22 (d, 2H), 7.28 (s, 1H), 7.36 (s, 1H),7.5 (d, 2H), 7.75 (br s, 1H).

EXAMPLE UU-2

Toluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-tert-butyl-phenyl)ester

The title compound was prepared according to the General Method 15 using(2-tert-butoxycarbonylamino-4-tert-butyl-5-mercapto-phenyl)-carbamicacid tert-butyl ester (prepared in Example TT-2; 16.9 g, 42.8 mmol),tosyl bromide (10.04 g, 42.76 mmol), pyridine (10 mL), and EtOAc (150mL). The crude product was purified by flash chromatography (5%-60%EtOAc in hexanes as eluents). ¹H-NMR (CDCl₃): δ 1.19 (s, 9H), 1.53 (s,18H), 2.42 (s, 3H), 6.42 (br s, 1H), 7.22 (d, 2H), 7.28 (s, 1H), 7.5 (m,3H), 7.87 (br s, 1H).

EXAMPLE VV-1

Toluene-4-thiosulfonic acid S-(4,5-diamino-2-isopropyl-phenyl)ester

Toluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-isopropyl-phenyl)ester (preparedin Example UU-1; 8.88 g, 16.6 mmol) was dissolved in CH₂Cl₂ (25 mL), andHCl gas was bubbled through the solution for 15 minutes. The reactionmixture was stirred at room temperature for 90 minutes. The solventswere evaporated, and the residue was dissolved in MeOH (10 mL) andtreated with pH 7.5 buffer. The precipitate that formed was filtered anddried. MS(APCI): 337 (M+H).

EXAMPLE VV-2

Toluene-4-thiosulfonic acid S-(4,5-diamino-2-tert-butyl-phenyl)ester

The title compound was prepared as described in Example VV-1 fromtoluene-4-thiosulfonic acidS-(4,5-bis-tert-butoxycarbonylamino-2-tert-butyl-phenyl)ester (preparedin Example UU-2; 15 g, 28 mmol), CH₂Cl₂ (100 mL), and HCl gas. MS(APCI):351 (M+H).

EXAMPLE BB-19

Toluene-4-thiosulfonic acid S-(6-isopropyl-3H-benzoimidazol-5-yl)

Toluene-4-thiosulfonic acid S-(1,2-diamino-5-isopropyl-phenyl)ester(prepared in Example VV-1; 0.5 g) was dissolved in 96% formic acid (0.5mL) and refluxed for 3 hours. After cooling, toluene (10 mL) and water(5 mL) were added. The organic layer was concentrated; the residue wastaken in EtOAc (20 mL), washed with H₂O, and dried (MgSO₄).Concentration gave the crude title compound which was purified by flashchromatography (20%-100% EtOAc in hexanes to 2%-8% MeOH in CH₂Cl₂ aseluents). MS(APCI): 347 (M+H).

EXAMPLE BB-20

Toluene-4-thiosulfonic acid S-(6-tert-butyl-3H-benzoimidzol-5-yl)ester

The title compound was prepared using the procedure outlined in ExampleBB-19 from toluene-4-thiosulfonic acidS-(1,2-diamino-5-tert-butyl-phenyl)ester (prepared in Example VV-2; 0.5g), and 96% formic acid (0.5 mL) The crude product was purified by flashchromatography (20%-100% EtOAc in hexanes to 2%-8% MeOH in CH₂Cl₂ aseluents). MS(APCI): 361 (M+H).

EXAMPLE BB-21

Toluene-4-thiosulfonic acidS-(6-tert-butyl-2-oxo-2,3-dihydro-1H-benzoimidzol-5-yl)ester

Toluene-4-thiosulfonic acid S-(4,5-diamino-2-tert-butyl-phenyl)ester(prepared in Example VV-2; 0.4 g, 1.2 mmol) and triphosgene (0.12 g,0.41 mmol) were taken in THF (30 mL). To it triethylamine (1 mL) wasadded. The reaction mixture was kept at 90° C. for 1.5 hours. The crudereaction mixture was subjected to flash silica gel chromatography (EtOActo 2%-10% MeOH in CH₂Cl₂ as eluents). MS(APCI): 375 (M−H).

Preparation of 2-substitued-Indoles for the Synthesis of BB-22

EXAMPLE WW

4-tert-Butyl-1-methyl-2-nitrobenzene

Nitration was performed as described in General Method 12 usingtert-butyl-4-methylbenzene (25 g), concentrated H₂SO₄ (92 g), 70% HNO₃(82 g), and H₂O (25 g). The crude product was purified via distillationunder vacuum.

EXAMPLE XX

3-(4-tert-Butyl-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester

The title compound was prepared by adapting the procedure described byGagliardi S., et al., in J. Med. Chem., 1998;41:1568 using potassium(1.66 g, 42.4 mmol), Et₂O (200 mL), EtOH (10 mL), diethyl oxalate (7.56g, 51.8 mmol), and 4-tert-butyl-1-methyl-2-nitrobenzene (prepared inExample WW; 10.0 g, 51.8 mmol). MS(APCI): 294 (M+H).

EXAMPLE YY

6-tert-Butyl-1H-indole-2-carboxylic acid ethyl ester

A mixture of 3-(4-tert-butyl-2-nitro-phenyl)-2-oxo-propionic acid ethylester (prepared in Example XX; 9.1 g, 31 mmol), iron powder (15.3 g, 274mmol). EtOH (70 mL), and glacial AcOH (70 mL) was refluxed for 2 hours.After cooling, the resulting mixture was evaporated. THF (100 mL) wasadded to the residue, and the suspension was filtered on florisil,eluting with a large amount of THF. The solvents were evaporated, andthe residue was purified by flash silica gel chromatography (5%-30%EtOAc in hexanes as eluents). MS(APCI): 246 (M+H).

EXAMPLE ZZ

6-tert-Butyl-5-thiocyanato-1H-indole-2-carboxylate ethyl ester

The title compound was prepared according to General Method 13 using6-tert-butyl-1H-indole-2-carboxylic acid ethyl ester (prepared inExample YY; 3.5 g, 14 mmol), ammonium thiocyanate (1.63 g, 21.4 mmol),bromine (3.42 g, 21.4 mmol), and MeOH (50 mL). The crude product waspurified by flash silica gel chromatography (5%-50% EtOAc in hexanes aseluents). MS(APCI): 301 (M−H).

EXAMPLE AAA

(6-tert-Butyl-5-mercapto-1H-indole-2-carboxylic acid ethyl ester

The title compound was prepared according to the general Method 14busing (6-tert-butyl-5-thiocyanato-1H-indole-2-carboxylic acid ethylester (prepared in Example ZZ; 0.25 g, 0.83 mmol), sodium hydrogensulfide (0.13 g, 2.48 mmol), sodium borohydride (0.188 g, 4.98 mmol),MeOH (5 mL), and AcOH (1 mL). MS(APCI): 278 (M+H).

EXAMPLE BB-22

6-tert-Butyl-5-(toluene-4-sulfonylsulfanyl)-1H-indole-2-carboxylic acidethyl ester

The title compound was prepared according to General Method 15 using(6-tert-Butyl-5-mercapto-1H-indole-2-carboxylic acid ethyl ester(prepared in Example AAA), pyridine, tosyl bromide, carbontetrachloride, and EtOAc.

Preparation of Quinoxalones for the Synthesis of BB-23

EXAMPLE BBB

(5-tert-Butyl-2-nitro-4-thiocyanatophenyl)-oxalmic acid methyl ester

5-tert-Butyl-2-nitro-4-thiocyanato-phenylamine (prepared in ExampleQQ-2; 2.5 g, 10.0 mmol) and methyl chloroxoacetate (5 mL) were dissolvedin CH₂Cl₂ (50 mL) and treated with pyridine (5 mL.) The reaction mixturewas stirred at room temperature overnight, quenched with saturatedNaHCO₃ solution, and diluted with EtOAc (100 mL). The organic layer waswashed with dil HCl and brine, dried (MgSO₄), and concentrated. Thecrude product was used without purification. MS(APCI): 336 (M−H).

EXAMPLE CCC

6-tert-Butyl-7-thiocyanato-1,4-dihydro-quinoxaline-2,3-dione

(5-tert-Butyl-2-nitro-4-thiocyanatophenyl)-oxalmic acid methyl ester(prepared in Example BBB; 3.91 g, 11.6 mmol) was taken up in THF (100mL) and treated with Raney nickel (1 g). The reaction mixture was shakenin a hydrogen atmosphere (50 psi). The catalyst was filtered; thefiltrate was concentrated, and the residue was triturated withEtOAc/hexanes to obtain the title compound. MS(APCI): 274 (M−H).

EXAMPLE DDD

6-tert-Butyl-7-mercapto-1,4-dihydro-quinoxaline-2,3-dione

The title compound was prepared according to General Method 14b using6-tert-butyl-7-thiocyanato-1,4-dihydro-quinoxaline-2,3-dione (preparedin Example CCC; 1.5 g, 9.1 mmol), sodium hydrogen sulfide (0.51 g, 27mmol), sodium borohydride (2.1 g, 55 mmol). MeOH (30 mL), H₂O (3 mL),and glacial AcOH (5 mL). The crude product was used withoutpurification. MS(APCI): 251 (M+H).

EXAMPLE BB-23

Toluene-4-thiosulfonic acidS-(7-tert-butyl-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)ester

The title compound was prepared according to the General Method 15 using6-tert-butyl-7-mercapto-1,4-dihydro-quinoxaline-2,3-dione (prepared inExample DDD, 9.1 mmol), tosyl bromide (2.1 g, 9.1 mmol), pyridine (2mL), EtOAc (50 mL). The crude product was purified by flash silica gelchromatography (5%-10% MeOH in CH₂Cl₂) as eluents. MS(APCI): 405 (M+H).

General Method 16a. Coupling of the Dihydropyrone and the Thiotosylate

The appropriate dihydropyrone intermediate (1 equiv.) from Table F orTable J was added to a reaction flask followed by DMF (1-12 mL per mmolof dihydropyrone). Potassium carbonate (K₂CO₃) (4-8 equiv.) was addedfollowed by the appropriate thiotosylate reagent (1.1-1.5 eq.) fromTable K. The reaction was stirred at room temperature (2.5 hours toovernight). The reaction was worked up by pouring into a mixture ofEtOAc and either 1N HCl or saturated aqueous NH₄Cl. The layers wereseparated and the aqueous layer extracted again with EtOAc. The combinedorganic extracts were washed with brine, dried (MgSO₄), andconcentrated. The final compounds were purified via recrystallization,trituration, or silica gel gel chromatography.

General Method 16b. Coupling of the Dihydropyrone and the Thiotosylate

The appropriate dihydropyrone intermediate (1 equiv.) from Examples E-1to E-46 or Examples J-1 to J-12 and the appropriate thiotosylate reagent(1.0-1.5 equiv.) from Examples BB-1 to BB-14 were added to a reactionflask, followed by acetonitrile (1-12 mL per mmol of dihydropyrone) andtriethylamine (NEt₃; 2-4 equiv.) The reaction was stirred at roomtemperature (2.5 hours to overnight.) The NEt₃ and solvent wereevaporated, and the reaction was poured into a mixture of EtOAc andeither saturated aqueous NH₄Cl or water. The aqueous layer was extractedwith EtOAc; the combined organic extracts were dried (MgSO₄), andconcentrated. The final compounds were purified via recrystallization,trituration, or silica gel gel chromatography.

EXAMPLE 1

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using4-hydroxy-6-isopropyl-6-(2-pyridin-4-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-15; 0.8 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product wastriturated from Et₂O, mp 140-155° C. MS (APCI): 470 (M+H).

EXAMPLE 2

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-16; 0.92 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;1.01 mmol), potassium carbonate (3.67 mmol) in DMF (5 mL). The productwas triturated from Et₂O, mp 122-125° C. MS (APCI): 470 (M+H).

EXAMPLE 3

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using4-hydroxy-6-isopropyl-6-(2-pyridin-2-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-14; 0.8 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.9mmol), potassium carbonate (3.1 mmol) in DMF (5 mL). The product wastriturated from Et₂O, mp 100-110° C. MS (APCI): 470 (M+H).

EXAMPLE 4

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-18; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1mmol), potassium carbonate (4 mmol) in DMF (4 mL). The product was flashchromatographed over silica gel using 70:20:10 hexane:EtOAc:CH₂Cl₂, mp62-70° C. MS (APCI): 457 (M−H).

EXAMPLE 5

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using6-(2-furan-2-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-17; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.1mmol), potassium carbonate (4 mmol) in DMF (5 mL) mp 64-110° C. MS(APCI): 457 (M−H).

EXAMPLE 6

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one(Example E-19; 0.98 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-; 1.18mmol), potassium carbonate (3.93 mmol) in DMF (5 mL). Flashchromatographed over silica gel using 10:90 EtOAc:CH₂Cl₂, mp 57-59° C.MS (APCI): 461 (M−H).

EXAMPLE 7

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-20; 0.84 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.92 mmol), potassium carbonate (3.35 mmol) in DMF (4 mL). The productwas purified via flash chromatography over silica gel eluting with 10:90EtOAc:CH₂Cl₂, mp 63-70° C. MS (APCI): 475 (M+H).

EXAMPLE 8

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using4-hydroxy-6-isopropyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-21; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.2mmol), potassium carbonate (4 mmol) in DMF (3 mL). The product wasisolated via flash chromatography over silica gel using 10:90EtOAc:CH₂Cl₂, mp 73-77° C. MS (APCI): 475 (M+H).

EXAMPLE 9

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-23; 0.67 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.74 mmol), potassium carbonate (2.7 mmol) in DMF (5 mL), mp 76-80° C.MS (APCI): 503 (M−H).

EXAMPLE 10

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16b using4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-24; 1 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;1.05 mmol), NEt₃ (2.2 mmol) in acetonitrile (5 mL). The product waschromatographed over silica gel using 97.5:2.5 CH₂Cl₂:MeOH, mp 87-90° C.MS (APCI): 503 (M−H).

EXAMPLE 11

3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16b using4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-24; 1 mmol), toluene-4-thiosulfonic acidS-(4-amino-2-tert-butyl-5-methyl-phenyl)ester (Example BB-11; 1.05mmol), NEt₃ (2.2 mmol) in acetonitrile (5 mL). The product wastriturated from Et₂O, mp 107-115° C. MS (APCI): 488 (M−H).

EXAMPLE 12 (S)

(S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared as described in General Method 16a using(S)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example J-1 (S); 2.68 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;3.22 mmol), potassium carbonate (10.74 mmol) in DMF (5 mL), mp 64-70° C.MS (APCI): 475 (M+H).

EXAMPLE 13

(S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to the General Method 16ausing tolune-4-thiosulfonic acidS-(2-amino-5-tert-butyl-benzothiazol-6-yl)ester (Example BB-1; 0.6 g,1.53 mmol),(S)-4-hydroxy-6-isopropyl-6-phenylethyl-5,6-dihydro-pyran-2-one (ExampleJ-11 (S); 0.4 g, 1.53 mmol), potassium carbonate (0.8 g), and DMF (DMF;5 mL). The crude reaction mixture was purified by flash chromatography(25% EtOAc in hexanes to 50% EtOAc in hexanes to 10% MeOH in EtOAc aseluents), mp 186-188° C. MS (APCI): 497 (M+H).

EXAMPLE 14

(S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to the General Method 16busing (S)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one(Example J-11 (S); 0.5 g, 1.92 mmol), toluene-4-thiosulfonic acidS-(2-amino-5-isopropyl-benzothiazol-6-yl)ester (Example BB-3; 0.73 g,1.92 mmol), NEt₃ (0.39 g, 3.84 mmol), and acetonitrile (10 mL). Thecrude compound was purified by flash silica gel chromatography (25%EtOAc in hexanes to 100% EtOAc to 5% MeOH in EtOAc as eluents), mp197-199° C. MS (APCI): 483 (M+H).

EXAMPLE 15

6-[-2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16b using6-[(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one(Example E-27; 0.5 g, 1.8 mmol), toluene-4-thiosulfonic acidS-(5-isopropyl-benzothiazol-6-yl)ester (Example BB-4; 0.65 g, 1.8 mmol),NEt₃ (0.22 g, 2.16 mmol), and acetonitrile (10 mL). The crude compoundwas purified by flash silica gel chromatography (25% EtOAc in hexanes to100% EtOAc to 5% MeOH in EtOAc as eluents), mp 104-105° C. MS (APCI):486.

EXAMPLE 16

3-(2-Amino-5-isopropyl-benzothiazol-6-yl-sulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-phenethyl-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method]6b using6-[(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-27; 0.5 g, 1.8 mmol), toluene-4-thiosulfonic acidS-(2-amino-5-isopropyl-benzothiazol-6-yl)ester (Example BB-3; 0.68 g,1.8 mmol), NEt₃ (0.36 g, 3.6 mmol), and acetonitrile (20 mL). The crudecompound was purified by flash silica gel chromatography (25% EtOAc inhexanes to 100% EtOAc to 5% MeOH in EtOAc as eluents), mp 204-206° C. MS(APCI): 501 (M+H).

EXAMPLE 17

(S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-phenethyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a usingtoluene-4-thiosulfonic acidS-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester (Example BB-5;0.75 g, 1.92 mmol),(S)-4-hydroxy-6-isopropyl-6-phenylethyl-5,6-dihydro-pyran-2-one (ExampleJ-11 (S); 0.5 g, 1.92 mmol), potassium carbonate (1.0 g), and DMF (5mL). The crude reaction mixture was purified by flash chromatography(25% EtOAc in hexanes to 50% EtOAc in hexanes to 5% MeOH in EtOAc aseluents), mp 160-162° C. MS (APCI): 497 (M+H).

EXAMPLE 18

(S)-3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a usingtoluene-4-thiosulfonic acidS-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester (Example BB-5;0.35 g, 1.27 mmol),(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10; 0.35 g. 1.27 mmol), potassium carbonate (0.7 g), and DMF(5 mL). The crude reaction mixture was purified by flash chromatography(20% EtOAc in hexanes to 50% EtOAc in hexanes to 5% MeOH in EtOAc aseluents), mp 232-234° C. MS (APCI): 513 (M+H).

EXAMPLE 19

(S)-(6-{4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-isopropyl-7-methyl-benzothiazol-2-yl)-carbamicacid methyl ester

The title compound was prepared according to General Method 16a usingtoluene-4-thiosulfonic acidS-[2-(methyloxycarbonyl)amino]-4-isopropyl-7-methyl-benzothiazol-6-yl)ester(Example BB-6; 0.65 g, 1.5 mmol),(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10 (S); 0.4 g, 1.5 mmol), potassium carbonate (0.7 g), andDMF (5 mL). The crude reaction mixture was purified by flashchromatography (30% EtOAc in hexanes to 100% EtOAc as eluents), mp150-151° C. MS (APCI): 571 (M+H).

EXAMPLE 20

(S)-3-(2-Amino-6-tert-butyl-benzothiazol-4-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a usingtoluene-4-thiosulfonic acidS-(2-amino-6-tert-butyl-benzothiazol-4-yl)ester (Example BB-7; 0.28 g,0.73 mmol),(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10 (S); 0.2 g, 0.73 mmol), potassium carbonate (0.7 g), andDMF (5 mL). The crude reaction mixture was purified by flashchromatography (30% EtOAc in hexanes to 100% EtOAc to 10% MeOH in CH₂Cl₂in as eluents), mp 168-179° C. MS (APCI): 513 (M+H).

EXAMPLE 21

(S)-3-(3-tert-Butyl-benzo[b]thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a using(S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example J-10 (S); 0.052 g, 0.19 mmol), toluene-4-thiosulfonic acidS-(3-tert-butyl-benzo[b]thiophen-2-yl)ester (Example BB-8; 0.080 g, 0.21mmol), potassium carbonate (0.029 g, 0.21 mmol), and DMF (1.0 mL). Theproduct was purified via column chromatography (eluting with 1:1hexanes:EtOAc) to provide a solid, mp 207° C.

¹H NMR (DMSO-d₆): δ 0.86-0.92 (m, 6H), 1.56 (s, 9H), 1.85-1.95 (m, 2H),2.09-2.21 (m, 3H), 2.52 (d, 1H), 2.92 (d, 1H), 6.62 (d, 2H), 6.93 (d,2H), 7.12 (t, 1H), 7.21 (t, 1H), 7.40 (d, 1H), 7.89 (d, 1H), 9.14 (s,1H).

EXAMPLE 22

3-(3-tert-Butyl-benzo[b]thiophen-2-yl-sulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a using4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one(Example E-34; 0.20 g, 0.73 mmol), toluene-4-thiosulfonic acidS-(3-tert-butyl-benzo[b]thiophen-2-yl)ester (Example BB-8; 0.302 g,0.803 mmol), potassium carbonate (0.11 g, 0.80 mmol), and DMF (2.0 mL).The product was purified via column chromatography (eluting with EtOAc)to the title compound, mp 92-94° C.

¹H NMR (DMSO-d₆): δ 0.93-0.99 (m, 6H), 1.61 (s, 9H), 2.13-2.28 (m, 3H),2.47-2.71 (m, 3H), 2.99 (d, 1H), 4.50 (dd, 2H), 7.09-7.28 (m, 5H), 7.35(d, 1H), 7.42 (d, 1H), 7.93 (d, 1H).

EXAMPLE 23

4-Hydroxy-3-(5-hydroxymethyl-2-isopropyl-thiophen-3-ylsulfanyl)-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16b using4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-20; 0.200 g, 0.75 mmol), toluene-4-thiosulfonic acidS-[5-(tert-butyl-dimethyl-silanyloxymethyl)-2-isopropyl-thiophen-3-yl]ester(Example BB-9; 0.377 g, 0.83 mmol), NEt₃ (0.209 mL, 1.50 mmol), andacetonitrile (1.5 mL). As part of the purification, the silylether wascleaved by dissolving the crude coupled product in THF (50 mL) and thentreated with a 1.0 M THF solution of tetrabutylammoniumflouride (1.5 mL,1.5 mmol). After 30 minutes, the mixture was diluted with H₂O andextracted with EtOAc. The organic layers were then combined, dried(MgSO₄), and concentrated. The resulting residue was then submitted tocolumn chromatography (eluting with 3% MeOH in CH₂Cl₂) to provide thetitle compound, mp 52-54° C.

¹H NMR (CDCl₃): δ 0.96-1.03 (m, 6H), 1.32 (t, 6H), 1.92-2.09 (m, 2H),2.17-2.26 (m, 1H), 2.49 (d, 1H), 2.66 (t, 2H), 2.93 (d, 1H), 3.71(sept., 1H), 4.57 (s, 2H), 6.71 (s, 1H), 6.79 (d, 1H), 6.84 (bs, 1H),7.23-7.24 (m, 1H), 7.83 (s, 1H).

EXAMPLE 24

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a using4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one(Example E-1; 0.22 g, 0.78 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.33 g, 0.90 mmol), potassium carbonate (1.0 g, 7.2 mmol), and DMF (4mL). The product was chromatographed on silica gel, eluting with 10%MeOH in CH₂Cl₂, to give the title compound, mp 138-141° C.

¹H NMR (DMSO-d₆): δ 0.90-0.96 (m, 6H), 1.46 (s, 9H), 1.85 (s, 3H),1.95-2.00 (m, 2H), 2.15-2.23 (m, 4H), 2.70-2.82 (m, 3H), 2.93 (d of ABXq, 1H), 4.34 (s, 2H), 4.92 (br s, 1H), 6.66 (s, 1H), 7.24 (s, 1H), 8.79(s, 1H).

EXAMPLE 25

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a using4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one(Example E-2; 0.25 g, 0.95 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.42 g, 1.15 mmol), potassium carbonate (0.52 g, 3.76 mmol), and DMF (5mL). The product was chromatographed on silica gel, eluting with 5% MeOHin CH₂Cl₂, to give the title compound, mp 108-110° C.

¹H NMR (DMSO-d₆): δ 0.91-0.95 (m, 6H), 1.46 (s, 9H), 1.92 (s, 3H),2.18-2.24 (m, 3H), 2.77 (d of ABX q, 1H), 2.96 (d of ABX q, 1H), 3.06(br t, 2H), 4.34 (s, 2H), 4.90 (br s, 1H), 6.68 (s, 1H), 7.24 (s, 1H),7.57 (d, 1H), 7.67 (d, 1H).

EXAMPLE 26

3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one

The title compound was prepared according to General Method 16a using4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one(Example E-6; 0.33 g, 1.2 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.51 g, 1.4 mmol), potassium carbonate (0.48 g, 3.5 mmol), and DMF (5mL). The product was chromatographed on silica gel, eluting with 5% MeOHin CH₂Cl₂, to give the title compound, mp 98-100° C.

¹H NMR (DMSO-d₆): δ 0.86-0.92 (m, 6H), 1.42 (s, 9H), 1.87 (s, 3H),2.15-2.20 (m, 3H), 2.25 (s, 3H), 2.71 (d of ABX q, 1H), 2.83-2.95 (m,3H), 4.30 (s, 2H), 4.89 (br s, 1H), 6.64 (s, 1H), 7.04 (s, 1H), 7.20 (d,1H).

EXAMPLE 27

N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]-ethyl}-thiazol-2-yl)-acetamide

The title compound was prepared according to General Method 16a usingN-{4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide(Example E-13; 0.49 g, 1.5 mmol), toluene-4-thiosulfonic acidS-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2;0.66 g, 1.8 mmol), potassium carbonate (0.83 g, 6.0 mmol), and DMF (5mL). The product was chromatographed on silica gel, eluting with 5% MeOHin CH₂Cl₂, to give the title compound, mp 128-130° C.

¹H NMR (DMSO-d₆): δ 0.86-0.92 (m, 6H), 1.42 (s, 9H), 1.85 (s, 3H), 2.05(m, 5H), 2.17 (m, 1H), 2.59-2.67 (m, 3H), 2.92 (d of ABX q, 1H),) 4.30(s, 2H), 4.89 (br s, 1H), 6.25 (s, 1H), 6.75 (s, 1H), 7.20 (d, 1H),11.92 (br s, 1H), 12.00 (s, 1H).

TABLE L Final Dihydropyrones

Chirality Melting Exam- at Point Mass Spe ple Ar₂ C-6 Ar₁ General Method(° C.) (APCI) 28

±

16a 103-105 490(M + H) 29

±

16a 120-124 476(M + H) 30

±

16a 118-121 490(M + H) 31

±

16a 105-108 490(M + H) 32

±

16b 97-110 518(M + H) 33

±

16b 109-112 518(M + H) 34

±

16b 108-112 518(M + H) 35

±

16a 93-98 460(M + H) 36

±

16a 96-101 453(M + H) 37

±

16a 90-96 38

±

16a 104-106 490(M + H) 39

±

16a 110-117 40

±

16a 136-138 459(M + H) 41

±

16a 134-135 444(M + H) 42

±

16a 221-223 471(M + H) 43

±

16a 120-122 456(M + H) 44

±

16a 145-148 486(M + H) 45

±

16a 137-140 471(M + H) 46

±

16a 115-118 476(M + H) 47 Ph S

16b 197-199 468(M + H) 48

S

16b 142 483(M) 49

±

16a 158-160 50

S

16a 232-234 513(M + H) 51

S

16b 204-206 52

R

16a 73-85 475(M + H) 53

±

16b 107-109 551(M + H) 54

±

16a 118-123 55

±

16a 80-87 56

±

16a 70-73 57

±

16a 461(M + H) 58

±

16a 89-91 489(M + H) 59

±

16a 669 60

|

16a 663 61

±

16a 95-96 508(M + H) 62

±

16b 107-113 488(M − H) 63

S

16a 115 487(M − H) 64

±

16a 86-90 487(M − H) 65

±

16a 98-101 472(M − H) 66

±

16a 489(M + H) 67

±

16a 104-106 488(M − H) 68

±

16a 104-105 498(M + H) 69

±

16a followed by NaOH deprotection 125-126 494(M + H) 70

S

16a 138-140 647(M + H) 71

S

16a 171-173 580(M + H) 72

S

16a followed by NaOH deprotection 103-105 480(M + H) 73

S

16a followed by NaOH deprotection 123-125 464(M + H) 74

S

16a 122-124 515(M + H) 75

S

16a 222-224 451(M + H) 76

S

16a 158-160 467(M + H) 77

S

16a 203-205 465(M + H) 78

S

16a 232-234 481(M + H) 79

S

16a 152-153 573(M − H) 80

S

16a 192-194 536(M + H) 81

S

Saponification of Example 80 with LiOH 123-125 506(M − H) 82

±

16a 190-192 503(M + H) 83

±

16a 193-195 515(M + H) 84

±

16a 180-182 529(M + H) 85

S

16a 173-175 533(M + H) 86

S

16a 175-177 539(M + H) 87

S

16a 221-222 668(M + H) 88

S

16a >173 529(M + H) 89

±

16a followed by NH₃/NeOH deprotection 208-210 491(M + 1) 90

+

16a followed by HCl (g) deprotection 482(M + 1) 91

+

16a followed by HCl (g) deprotection 472(M + 1) 92

±

16a 155-157 659(M − 1)

The Table L above shows the compounds of the invention as racemic;however, the R and S forms are within the scope of the invention. The Sform is the preferred.

The compound names corresponding to Examples 28-60 in Table L above are:

-   -   Example 28:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 29:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one:    -   Example 30:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 31:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 32:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 33:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-isopropyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 34:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-isopropyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 35:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 36:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 37:        3-(2-tert-Butyl-4-hydroxy-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 38:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 39:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 40:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 41:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-[2-(1H-pyrazol-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 42:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 43:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyrimidin-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 44:        6-[2-(2-Amino-pyrimidin-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 45:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(2-amino-pyrimidin-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 46:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 47:        (S)-4-Hydroxy-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-6-phenethyl-5,6-dihydro-pyran-2-one;    -   Example 48:        (S)-4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;    -   Example 49:        3-(2-Amino-7-isopropyl-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 50:        (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 51:        (S)-3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 52:        (R)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 53:        3-(2-Amino-5-isopropyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 54:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 55:        3-(2-tert-Butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 56:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(tetrahydro-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 57:        3-(2-tert-Butyl-4-hydroxymethyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 58:        3-[2-tert-Butyl-4-(2-hydroxy-ethyl)-5-methyl-phenylsulfanyl]-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 59: 5-Trifluoromethyl-pyridine-2-sulfonic acid        {5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;        and    -   Example 60: 5-Trifluoromethyl-pyridine-2-sulfonic acid        {5-tert-butyl-4-[4-hydroxy-6-isopropyl-2-oxo-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-2-methyl-phenyl}-amide;    -   Example 61:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 62:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 63:        (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 64:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 65:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 66:        3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   Example 67:        3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 68:        4-Hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;    -   Example 69:        4-Hydroxy-3-(6-tert-butyl-indol-5-ylsulfanyl)-6-[2-(2-hydroxymethyl-phenyl)-ethyl]6-isopropyl-5,6-dihydropyran-2-one;    -   Example 70:        (S)-N-[6-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-[2-(4-hydroxy-phenyl)ethyl]-5,6-dihydro-2H-pyran-3-ylsulfanyl)-indolin-1-yl]-(4-cyanophenyl)sulfonamide;    -   Example 71:        (S)-6-tert-Butyl-5-{4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-yl        sulfanyl}-indole-1-carboxylic acid tert-butyl ester;    -   Example 72: (S)-3-(6-tert-Butyl-indol-5-yl-sulfanyl)-4-hydroxy        6-[2-(4-hydroxy-phenyl)-ethyl]6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 73:        (S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;    -   Example 74:        (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 75:        (S)-4-Hydroxy-6-isopropyl-3-(6-isopropyl-3H-benzoimidazol-5-ylsulfanyl)-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;    -   Example 76:        (S)-5-(4-Hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-6-isopropyl-1,3-dihydro-benzoimidazol-2-one;    -   Example 77:        (S)-3-(6-tert-Butyl-3H-benzoimidazol-5-yl-sulfanyl)-4-hydroxy-6-isopropyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;    -   Example 78:        (S)-5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-phenethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1,3-dihydro-benzoimidazol-2-one;    -   Example 79:        (S)-N-[5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl]-methanesulfonamide;    -   Example 80:        6-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1H-indole-2-carboxylic        acid ethyl ester;    -   Example 81:        6-tert-Butyl-5-(4-hydroxy-6-isopropyl-2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-1H-indole-2-carboxylic        acid;    -   Example 82:        3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[(2-(3-thiophenyl)-ethyl)-5,6-dihydro-pyran-2-one;    -   Example 83:        (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 84:        3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 85:        (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3,5-difluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 86:        (S)-N-[5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-phenethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl]-acetamide;    -   Example 87:        (S)-N-{5-tert-Butyl-6-(4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl-5,6-dihydro-2H-pyran-3-ylsulfanyl)-benzothiazol-2-yl}-4-cyanobenzenesulfonamide;    -   Example 88:        (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-2-methyl-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 89:        6-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 90:        (S)-3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   Example 91:        (S)-3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-[(2-(3-thiophenyl)-ethyl)-5,6-dihydro-pyran-2-one;        and    -   Example 92:        4-(6-tert-Butyl-5-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-2,3-dihydro-indole-1-sulfonyl)-benzonitrile.

Other compounds which can be prepared by the above methods include:

-   -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-thiophen-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-thiophen-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-cyclopentyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(3-hydroxymethyl-furan-2-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-furan-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(2-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(3-methyl-furan-2-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenyl        sulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-furan-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(2-Cyclopentyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one,    -   3-(6-tert-Butyl-1-hydroxy-indan-5-ylsulfanyl)-6-(2-furan-3-yl-ethyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(4-hydroxymethyl-thiazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(5-hydroxymethyl-thiazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(5-methyl-thiazol-4-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   6-[2-(2-Amino-thiazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(2-Amino-thiazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-4-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-5-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-isothiazol-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-[2-(4-methyl-oxazol-5-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-5-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(1H-benzoimidazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(1H-Benzoimidazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-5-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(3-Amino-1H-indazol-5-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(1H-indazol-4-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-[2-(3-amino-1H-indazol-4-yl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(3-Amino-1H-indazol-4-yl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(5-tert-Butyl-2-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-tert-Butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(4-tert-Butyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(4-Amino-phenyl)-ethyl]-3-(2-tert-butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-5-methyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(4-Amino-phenyl)-ethyl]-3-(4-tert-butyl-5-hydroxymethyl-thiophen-3-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   6-[2-(4-Amino-phenyl)-ethyl]-3-(3-tert-butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-4-hydroxymethyl-5-methyl-thiophen-2-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;    -   N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-acetamide;    -   N-(7-tert-Butyl-6-{6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;    -   N-(7-tert-Butyl-6-{4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-2-oxo-5,6-dihydro-2H-pyran-3-ylsulfanyl}-4-methyl-benzothiazol-2-yl)-methanesulfonamide;    -   3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-6-[2-(4-fluoro-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-6-hydroxymethyl-5-methyl-pyridin-3-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(3-tert-Butyl-2-hydroxymethyl-6-methyl-pyridin-4-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-2,3-dihydro-1H-indol-5-yl        sulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(6-tert-Butyl-1H-indol-5-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-1,2,3,4-tetrahydro-quinolin-6-ylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one;    -   N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-acetamide;    -   N-{7-tert-Butyl-6-[4-hydroxy-6-isopropyl-2-oxo-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-2H-pyran-3-ylsulfanyl]-4-methyl-benzothiazol-2-yl}-methanesulfonamide;    -   3-(7-tert-Butyl-2-dimethylamino-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-S,        6-dihydro-pyran-2-one;    -   3-(7-tert-Butyl-2-hydroxy-4-methyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-n-pentyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(2-tert-Butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-n-pentyl-6-(2-thiophen-2-yl-ethyl)-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-cyclohexyl-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-6-cyclopentyl-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-5,6-dihydro-pyran-2-one;    -   3-(4-Amino-2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-n-pentyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-4-hydroxy-6-n-pentyl-6-phenethyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclohexyl-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclopentyl-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one;    -   (S)-4-Hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-propyl-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;    -   (S)-6-Cyclohexyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;    -   (S)-6-Cyclopentyl-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-3-(5-isopropyl-benzothiazol-6-ylsulfanyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-propyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-6-cyclohexyl-4-hydroxy-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-6-cyclopentyl-4-hydroxy-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(6-tert-Butyl-1H-indol-5-yl-sulfanyl)-4-hydroxy-6-pentyl-6-(2-phenethyl)-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-propyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-6-pentyl-5,6-dihydro-pyran-2-one;    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclohexyl-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one;        and    -   (S)-3-(2-Amino-5-tert-butyl-benzothiazol-6-ylsulfanyl)-6-cyclopentyl-6-[2-(3-fluoro-phenyl)-ethyl]-4-hydroxy-5,6-dihydro-pyran-2-one.

The compounds of the present invention were evaluated for their in vitroinhibition of HIV protease and for their antiviral efficacy in HIVinfected lymphocytes and the results shown in Table 1. Two referenceagents are included and are shown below.

The two Reference Agents 1 and 2 are the two best compounds as disclosedby Hagen, et al. J. Med. Chem., 1997;40:3707-3711). These referencecompounds were recognized to have particularly good antiviral activitydue in part to the polar substituents placed on the phenyl andphenethylmoieties. In a subsequent disclosure by S. Vander Roest, etal., 37^(th) Interscience Conference on Antimicrobial Agents andChemotherapy, Sep. 28-Oct. 1, 1997. Toronto, Canada Abstract I-84), itwas revealed that Reference Agents 1 and 2 had comparatively goodpharmacokinetics in mice relative to a large series of related polarsubstituted phenyl and phenethyl derivatives. Thus, Reference Agents 1and 2, represent excellent comparative agents for the compounds of thecurrent invention both in vitro and in vivo.

The following sections provide the experimental methodology for the invitro and in vivo assays employed to demonstrate the efficacy andadvantages of the compounds of the current invention.

HIV Protease Assay

Materials

Recombinant HIV-1 protease (>96% purity) and HIV protease substrate III(the undecapeptide H-His-Lys-Ala-Arg-Val-Leu-Nph-Glu-Ala-Nle-Ser-NH₂,97% purity) were purchased from Bachem Bioscience, Inc. (King ofPrussia, Pa.).

Method

The methods employed follow the procedures of Tummino, et al., Archivesof Biochemistry and Biophysics, 1995;316:523). For determination of Kivalues, HIV-1 protease, 6.0 nM final concentration, was added to asolution containing inhibitor, 40 μM substrate III and 1.0% Me₂SO inassay buffer: 80 mM MES, 160 mM NaCl, 1.0 mM EDTA 0.1% polyethyleneglycol (Mr 8000) pH 6.2 at 37° C. (total volume, 100 & 1). Polyethyleneglycol was used in the assay in place of glycerol since the former wasreported to be a more effective stabilizing agent in the protease(Jordan, et al., J. Biol. Chem., 1992;267:20028). The final inhibitorconcentrations used were 0 (0.1, 0.2, in some experiments), 0.5, 1, 2,5, 10, 20, 50, and 100 μM. The solution was mixed, incubated for 5minutes and the reaction quenched by addition of trifluoracetic acid. 2%final. The (leu-p-nitro-phe) bond of the substrate is cleaved by theenzyme and substrate and products separated by reverse-phase HPLC.Absorbance was measured at 220 nm, peak areas determined, and percentageconversion to product used to calculate percentage control (=[%conversion (+inhibitor)/% conversion (−inhibitor)]×100).

Cellular Infection Assay

Compounds were tested in lymphocyte derived CEM cells using the XTTcytopathic procedures and were performed at Southern Research Institute(Buckheit, et al., Antiviral Res., 1993;21:247; see also Weislow, et al.J. Nat. Cancer Inst., 1989;81:577). Compound concentrations were 0.32,1, 3.2, 10, 32, and 100 uM. The EC₅₀ represents the concentration ofagent which reduces HIV cytopathic effects 50% relative to untreatedcontrol. Cellular toxicity of the agents are estimated from the TC₅₀which represents the concentration of the agent which inhibits 50% ofthe viability of uninfected cells.

Table 1 contains the results of the HIV protease assay Ki and theantiviral efficacy (EC₅₀, TC₅₀, TI) screening, where TI is thetherapeutic index (TC₅₀/EC₅₀).

Mouse Blood Levels

Charles River CD-1 mice were dosed with a 25 mg/kg drug solution orallyby gavage. For oral dosing the compounds were dissolved in 0.1N NaOH(20% final volume) and then 0.5% methylcellulose (80% final volume) wasadded. Blood was drawn and pooled from 5 mice at each time point viaheart puncture and was placed in a 15 mL centrifuge tube containingheparin. The plasma stored in 200 μL aliquots at −80° C. until assayed.

Plasma was thawed at room temperature and then 400 μL of acetonitrilewas added to each vial and vortexed. Following centrifugation thesupernatant was removed and evaporated in a nitrogen evaporator at 48°C. Residue was then resolublized in 200 μL of a 75% water/25% CH₃CNsolution for HPLC analysis. HPLC analysis used a Zorbax RX-C8 column(4.6×150 mm) with a 25 mM potassium phosphate buffer with 0.1% TFA, pH3.0. Mobile phases consisted of varying percentages of two buffermixtures: Buffer A—90% buffer, 10% CH₃CN, and Buffer B—30% buffer, 70%CH₃CN. Absorbance was determined at a wavelength of 260 nM.

A standard curve ranging from 0.5 to 50 μg/mL was used for each drugtested. Ten times final concentration solutions of drug in water wereprepared from stock solutions of 1 mg/mL drug in DMSO. The final 1:10dilution was then done in mouse plasma obtained from mice describedabove.

The results from testing the reference agents and the compounds of thisinvention are shown in Table 2.

Rat and Dog Blood Levels

The procedure for pharmacokinetic analysis in dogs and rats was similar.For dog studies, two dogs received a single oral 10 mg/kg dose of theHIV protease inhibitor as a solution. The protease inhibitor wasdissolve in 0.1N NaOH followed by buffering or diluting with isotonicphosphate buffer or water depending on solubility. For rat studies, twomale rats received a single oral 10 mg/kg gavage dose of the HIVprotease inhibitor suspended in 0.5% methylcellulose. For the IVadministration, the compounds were dissolved in 0.1N sodium hydroxide ata concentration of 10 mg/ml. The IV dose was given bolus. Blood sampleswere collected prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12,and 24 hours postdose. Plasma samples were analyzed for the HIV proteaseinhibitor using a HPLC procedure. The method involved plasma proteinprecipitation with acetonitrile, reverse-phase chromatographicseparation of the HIV protease inhibitor and internal standard, andquantitation by UV detection. Some plasma samples were concentrated byevaporation prior to injection. Pharmacokinetic parameters weredetermined by noncompartmental analysis of individual rat-plasmaconcentration-time curves using WinNonlin. Maximum concentration (Cmax)and time for these to occur (tmax) were recorded as observed. Area underconcentration-time curve (AUC) values were obtained using the lineartrapezoidal rule. The results of the pharmacokinetic studies in dogs andrats are shown in Table 3.

Table 1 indicates that the compounds of the present invention have goodto excellent activity toward inhibiting the HIV protease enzyme (Ki's)as well as activity in HIV infected cells, protecting the cells from HIVpathogenicity at μM and sub-μM concentrations. The two reference agentsin Table 1, which represent the best of the hydroxylated and aminatedcompounds from the art, are wholly comparable to the compounds of thecurrent invention at the antiviral level. Yet the current inventionrelies not only on the antiviral activity but on the unexpected findingthat certain heterocycles could sufficiently mimic the polar groups ofthe reference agents while effecting significant gains inpharmacokinetic parameters due in part to reduced metabolism of theamines and phenols of the reference agents.

In Table 2, the results from mouse pharmacokinetic studies are shown forthe reference agents and certain of the compounds of the presentinvention. In Table 3, the oral pharmacokinetics of certain compoundsand the reference agents in rats and dogs are shown. Table 4 shows thepharmacokinetics in rats compared to the reference agents.

The results in Table 2 show a clear improvement in Cmax and T1/2 of thecompounds of the invention relative to the Reference Agents. The resultsfrom Table 3 show that the pharmacokinetic advantages of the compoundsof the current invention are not limited to mice but are manifest inrats and dogs. Such data all support the unexpected observation thatselect heterocycles mimic the polar hydroxylated and aminated phenylgroups, yet posses unexpectedly good pharmacokinetics relative to thebest Reference Agents.

TABLE 1 Inhibition of HIV-Protease and Antiviral Efficacy in a CEM CellInfection Assay Inhib of HIV Antiviral Efficacy Example Protease KI (nM)EC₅₀ (μM) TC₅₀ (μM) TI 1 1.5 1.5 296 197 2 0.9 0.9 216 240 4 0.35 1.0199 199 5 0.78 0.75 190 253 7 0.17 0.3 110 366 8 0.35 0.5 80.5 161 90.19 1.8 210 117 11 0.23 0.29 133 458 12 0.07 0.14 91 650 13 0.28 42 15214 0.67 2.5 75 30 16 11 114 10.4 17 2.7 42 16 18 1.1 117 105 22 0.85 1.566 43 24 0.37 164 443 25 0.57 0.7 216 308 26 0.45 0.8 171 213 28 0.241.9 229 120 32 1.6 23 91 4 33 1.4 101 72 35 0.88 1.5 72 48 36 1.7 2.2170 77 37 0.37 4.2 100 24 38 0.33 1.1 124 113 40 0.28 5.6 >320 >57 416.5 20 195 10 42 1.3 >200 >159 48 0.4 0.37 29 78 55 1.7 8.3 66 8 56 1110 210 21 59 0.08 0.6 66 110 61 0.98 0.68 46 68 65 1.2 1.1 60 54 69 0.670.18 55 306 70 0.82 1.3 8 6 73 0.54 0.61 42 69 79 2.1 2.2 125 56 82 1.10.7 76 109 83 0.44 0.26 61 235 84 0.8 0.47 93 198 89 0.95 3.5 >200 >57Ref 1 0.43 0.5 >100 >200 Ref 2 0.22 0.6 >100 >166

TABLE 2 Pharmacokinetic Evaluation of HIV Protease Inhibitors in MiceFollowing an Oral Dose of 25 mg/kg Cmax^(a) T ½^(b) Example (μM) (hr)Ref 1 23 2.2 Ref 2 17 2.0 2 46 7.3 4 54 5.6 7 40 3.5 12 95 9.5 25 33 3.3^(a)The maximum concentration reached within the plasma. ^(b)The halflife of the agents.

TABLE 3 Pharmacokinetic Evaluation of HIV Protease Inhibitors in Ratsand Dogs Following an Oral Dose of 10 mg/kg Rats Dogs Cmax^(a) T ½^(b)Cmax T ½^(b) Example (μM) (hr) (μM) (hr) Ref 1 16 3.4 140 1.25 Ref 2 3.40.55  40 0.52 12 30 11.5 149 1.75 13 5.1 8.6 — — 25 6.0 12.0 — — ^(a)Themaximum concentration reached within the plasma. ^(b)The half life ofthe agents.

TABLE 4 Pharmacokinetic Evaluation of HIV Protease Inhibitors in RatsFollowing an IV Dose of 10 mg/kg C(0) T ½^(a) Example (μM) (hr) Ref 1 863.7 Ref 2 100 3.9 12 160 12.0 25 120 8.0 69 335 4.5 83 199 4.0 ^(a)Thehalf life of the agents.

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof wherein R₁ is H, astraight or branched alkyl of 1-6 carbons or a carbocycle of 3-6carbons; R₂ is H, a straight or branched alkyl of 1-5 carbons; R₃ is H,(CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, (CR′₂)_(n)NR′COR, (CR′₂)_(n)CO₂R,(CR′₂)_(n)OCOR, (CR′₂)_(n)CON(R)₂, (CR′₂)_(n)OCON(R)₂, (CR′₂)_(n)R,(CR′₂)_(n)NR′CON(R)₂, (CR′₂)_(n)NR′CO₂R, (CR′₂)_(n)OSO₂N(R)₂,(CR′₂)_(n)NR′SO₂OR, (CR′₂)_(n)NR′SO₂N(R)₂, (CR′₂)_(n)OSO₂R,(CR′₂)_(n)NR′SO₂R, (CR′₂)_(n)SO_(p)R, (CR′₂)_(n)NR′CSN(R)₂,(CR′₂)_(n)NR′C(NR′)N(R)₂, (CR′₂)_(n)SO₂N(R)₂, (CR′₂)_(n)C(NR′)N(R)₂,(CR′₂)_(n)COR, O(CR′₂)_(m)OR, NR(CR′₂)_(m)OR, F, Cl, Br, CF₃, CN, or ═O;R₄, R₅, and R₆ are independently H, a straight or branched alkyl of 1-6carbons, a cycloalkyl of 3-6 carbons, (CR′₂)_(n)OR, (CR′₂)_(n)N(R)₂, F,Cl, Br, CN, CF₃, ═O, (CR′₂)_(p)NR′COR, (CR′₂)_(p)SO_(p)R, (CR′₂)_(p)R,(CR′₂)_(p)OCOR, O(CR′₂)_(m)OR, NR(CR′₂)_(m)OR, (CR′₂)_(p)NR′CON(R)₂,(CR′₂)_(p)OCON(R)₂, (CR′₂)_(p)NR′CO₂R, (CR′₂)_(p)COR, (CR′₂)_(p)CO₂R,(CR′₂)_(p)CON(R)₂, (CR′₂)_(p)NR′SO₂R, (CR′₂)_(p)SO₂N(R)₂,(CR′₂)_(p)NR′SO₂OR, (CR′₂)_(p)OSO₂N(R)₂, (CR′₂)_(p)NR′SO₂N(R)₂,(CR′₂)_(p)C(NR′)N(R)₂, (CR′₂)_(p)NR′C(NR′)N(R)₂, (CR′₂)_(p)Het; any twoof R₁-R₃ or R₄-R₆ may together form a ring of 5-6 total atoms which maycontain 0-3 heteroatoms; n is an integer of from 0 to 3; m is an integerof from 2 to 4; p is an integer from 0 to 2; R₇ is a straight orbranched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons; R isindependently H, a straight or branched alkyl of 1-4 carbons,(CH₂)_(n)Ph, or a (CH₂)_(n) heterocycle of 5-6 atoms containing 1-2heteroatoms and wherein the (R)₂ in N(R)₂ may form a heterocyclecontaining the nitrogen, all optionally substituted by F, Cl, Br, OR′,CN, CO₂R′, N(R′)₂, NR′COR′, CF₃, or ═O; R′ is independently H, astraight or branched alkyl of 1-4 carbons, or phenyl; R″ isindependently H, a straight or branched alkyl of 1-4 carbons, F, Cl, Br,OR′, or N(R′)₂; Ar₁ is Het; wherein Het is a heterocycle of from 5-6atoms having 1-4 heteroatoms selected from pyrrole, thiophene, oxazole,isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, or pyrazine, or a fusedheterocycle of from 9-10 atoms having from 1-3 heteroatoms selectedfrom; indole, indoline, benzothiophene, benzthiazole, benzoxazole,quinoline, isoquinoline, cinnoline, quinazoline and quinoxaline; and Ar₂is phenyl.
 2. A compound according to claim 1 wherein: R₁ is a straightor branched alkyl of from 1 to 4 carbons or a carbocycle of from 3 to 5carbons and R₂ is H or a straight or branched alkyl of from 1 to 3carbons.
 3. A compound according to claim 1 wherein: R₁ is H, methyl,ethyl, isopropyl, or t-butyl; R₂ is H or methyl; R₃ is H, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR, (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)NR′CON(R)₂, (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R,(CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)COR, O(CH₂)_(m)OR′,NR(CH₂)_(m)OR′, C(CH₃)₂OR′, F, Cl, Br, CF₃, or ═O; R₄, R₅, and R₆ areindependently H, a straight or branched alkyl of 1-6 carbons, acycloalkyl of 3-6 carbons, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, F, Cl, Br, CF₃,(CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂, (CH₂)_(p)OCON(R)₂,(CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂, (CH₂)_(p)NR′SO₂R,(CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂ (CH₂)_(p) Het wherein p is 0 to 2;any two of R₄-R₆ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms; R is H, a straight or branched alkyl of 1-4carbons, (CH₂)_(n)Ph, or a (CH₂)_(n) heterocycle of 5-6 atoms havingfrom 1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may form aheterocycle having nitrogen, all optionally substituted by F, Cl, Br,OR′, N(R′)₂, NR′COR′, or ═O; and Ar₁ is a heterocycle of 5-6 atomshaving from 1-4 heteroatoms selected from: pyrrole, thiophene, oxazole,isoxazole, thiazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole,tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperazine, piperidine, morpholine,thiomorpholine, oxolane, dioxane, sulfolane; or a fused heterocycle of9-10 atoms having 1-3 heteroatoms selected from: indole, indoline,benzothiophene, benzthiazole, benzoxazole, quinoline, isoquinoline,cinnoline, quinazoline and quinoxaline.
 4. A compound according to claim1 wherein: R₂ is H, methyl or ethyl or isopropyl; R₃ is H, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, (CH₂)_(n)NRCOR, (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)NR′CON(R)₂, (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R,(CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, O(CH₂)_(m)OR, NR(CH₂)_(m)OR′,C(CH₃)₂OR′, or ═O; R₄, R₅, and R₆ are independently H, a straight orbranched alkyl of 1-6 carbons, a cycloalkyl of 1-6 carbons, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, F, Cl, Br, ═O, (CH₂)_(p)NR′COR, (CH₂)_(p)NR′CON(R)₂,(CH₂)_(p)OCON(R)₂, (CH₂)_(p)NR′CO₂R, (CH₂)_(p)COR, (CH₂)_(p)CON(R)₂,(CH₂)_(p)NR′SO₂R, (CH₂)_(p)NR′SO₂OR, (CH₂)_(p)OSO₂N(R)₂, wherein p is 0to 2; R₄ and R₅ may together form a ring of 5-6 total atoms which maycontain 0-2 heteroatoms; R is H, a straight or branched alkyl of 1-4carbons, (CH₂)_(n)Ph, or a (CH₂)_(n) heterocycle of 5-6 atoms containing1-2 heteroatoms and wherein the (R)₂ in N(R)₂ may be a heterocyclehaving nitrogen, all optionally substituted by F, Cl, Br, OR′, N(R′)₂,NR′COR′, or ═O; and Ar₁ is thiophene, thiazole, pyridine,benzothiophene, benzthiazole, benzoxazole, quinoline or isoquinoline. 5.A compound according to claim 1 wherein: R₁ is H, methyl, ethyl,isopropyl, or t-butyl; R₂ is H or methyl; R₃ is H, (CH₂)_(n)OR,(CH₂)_(n)N(R)₂, (CH₂)_(n)NR′COR, (CH₂)_(n)CON(R)₂, (CH₂)_(n)OCON(R)₂,(CH₂)_(n)NR′CON(R), (CH₂)_(n)NR′CO₂R, (CH₂)_(n)OSO₂N(R)₂,(CH₂)_(n)NR′SO₂OR, (CH₂)_(n)NR′SO₂N(R)₂, (CH₂)_(n)OSO₂R,(CH₂)_(n)NR′SO₂R, (CH₂)_(n)SO₂R, (CH₂)_(n)NR′CSN(R)₂, (CH₂)_(n)COR,O(CH₂)_(m)OR, NR(CH₂)_(m)OR′, C(CH₃)₂OR′, F, Cl, Br, or ═O; R₄, R₅ andR₆ are independently H, methyl, ethyl, OH, CH₂OH, CH₂CH₂OH, F, Cl, NH₂;any two R₄-R₆ may form a ring of 5-6 atoms having from 1-2 heteroatoms;R is H, a straight or branched alkyl of 1-4 carbons, (CH₂)_(n)Ph, or a(CH₂)_(n) heterocycle of 5-6 atoms having from 1-2 heteroatoms or aheterocycle having a nitrogen, all optionally substituted by F, Cl, Br,OR′, N(R′)₂, NR′COR′, or ═O; and Ar₁ is thiophene, thiazole, pyridine,benzothiophene, benzthiazole, quinoline, or isoquinoline.
 6. A compoundaccording to claim 1 wherein: R₁ is H, methyl, ethyl, isopropyl, ort-butyl; R₂ is H or methyl; R₃ is H, (CH₂)_(n)OR, (CH₂)_(n)N(R)₂, or ═O;R₄, R₅, and R₆ are independently H, methyl, OH, CH₂OH, CH₂CH₂OH, NH₂, orF; R₇ is H, isopropyl, butyl, sec-butyl, cyclobutyl, cyclopentyl, orcyclohexyl; R is H, methyl, ethyl, phenyl, or CH₂Ph and wherein the (R)₂of N(R)₂ may be a heterocycle having a nitrogen; R″ is H, F, or CH₃; andAr₁ is thiophene, thiazole, pyridine, benzothiophene, benzthiazole,quinoline, or isoquinoline.
 7. A compound according to claim 1 wherein:R₁ is H, methyl, ethyl, isopropyl, or t-butyl; R₂ is H or methyl; R₃ isH, CH₂OH, NH₂, or ═O; R₄, R₅, and R₆ are independently H, OH, CH₂OH,NH₂, or F; R₇ is isopropyl, sec-butyl, isobutyl, or cyclopentyl; R is H,methyl, ethyl, Ph, CH₂Ph, and wherein the (R)₂ in N(R)₂ may be aheterocycle having a nitrogen; R″ is H, F, or CH₃; and Ar₁ is thiophene,thiazole, pyrazole, or pyridine.
 8. A pharmaceutical composition for thetreatment of infection or disease caused by a retrovirus, whichcomprises a therapeutically effective amount of a compound of claim 1 toprovide an effective antiviral dosage of the compound in the range ofabout 1 to about 50 mg/kg-day or up to 3 g per day and apharmaceutically effective carrier.
 9. A method of treatment ofinfection or disease caused by a retrovirus, which comprisesadministering to a subject in need of such treatment a compound ofclaim
 1. 10. A method of treatment of infection or disease caused by aretrovirus, which comprises administering to a subject in need of suchtreatment a compound of claim 1 in combination with an HIV reversetranscriptase inhibitor.
 11. A method of treatment of infection ordisease caused by a retrovirus, which comprises administering to asubject in need of such treatment a compound according to claim 1 andanother antiretroviral agent.